Jump to content

Methamphetamine

This is a good article. Click here for more information.
Page semi-protected
From Wikipedia, the free encyclopedia
(Redirected from Medical meth)

"Meth" redirects here. For other uses, see Meth (disambiguation).
Methamphetamine
INN: Metamfetamine
A racemic image of the methamphetamine compound
A 3d image of the levo-methamphetamine compound A 3d image of the dextro-methamphetamine compound
Clinical data
Pronunciation/ˌmɛθæmˈfɛtəmiːn/
(METH-am-FET-ə-meen), /ˌmɛθəmˈfɛtəmiːn/
(METH-əm-FET-ə-meen), /ˌmɛθəmˈfɛtəmən/
(METH-əm-FET-ə-mən)[1]
Trade namesDesoxyn, others
Other namesN-methylamphetamine, N,α-dimethylphenethylamine, desoxyephedrine
AHFS/Drugs.comMonograph
Dependence
liability
Addiction
liability		Very High
Routes of
administration		By mouth, intravenous, intramuscular, subcutaneous, inhalation, insufflation, rectal, vaginal
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: 67%[4][5][6][7]
Intranasal: 79%[4][5]
Inhalation: 67–90%[4][5][6]
Intravenous: 100%[4][7]
Protein bindingVaries widely[8]
MetabolismCYP2D6[9][10] and FMO3[11][12]
Metabolites• Amphetamine
• Pholedrine
• N-Hydroxymethamphetamine
Onset of actionOral: 3 hours (peak)[4]
Intranasal: <15 minutes[4]
Inhalation: <18 minutes[4][5]
Intravenous: <15 minutes[4]
Elimination half-life9–12 hours (range 5–30 hours); irrespective of route[5][4]
Duration of action8–12 hours[6]
ExcretionPrimarily kidney
Identifiers
  • (RS)-N-methyl-1-phenylpropan-2-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.007.882 Edit this at Wikidata
Chemical and physical data
FormulaC10H15N
Molar mass149.237 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Melting point170 °C (338 °F) [13]
Boiling point212 °C (414 °F) at 760 mmHg[13]
  • CNC(C)Cc1ccccc1
  • InChI=1S/C10H15N/c1-9(11-2)8-10-6-4-3-5-7-10/h3-7,9,11H,8H2,1-2H3 checkY
  • Key:MYWUZJCMWCOHBA-UHFFFAOYSA-N checkY
  (verify)

Methamphetamine[note 1] (contracted from N-methylamphetamine) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational or performance-enhancing drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder (ADHD) and obesity.[23] It has also been researched as a potential treatment for traumatic brain injury.[7] Methamphetamine was discovered in 1893 and exists as two enantiomers: levo-methamphetamine and dextro-methamphetamine.[note 2] Methamphetamine properly refers to a specific chemical substance, the racemic free base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms, but the hydrochloride salt, commonly called crystal meth, is widely used. Methamphetamine is rarely prescribed over concerns involving its potential for recreational use as an aphrodisiac and euphoriant, among other concerns, as well as the availability of safer substitute drugs with comparable treatment efficacy such as Adderall and Vyvanse.[23] Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.[23]

Both racemic methamphetamine and dextromethamphetamine are illicitly trafficked and sold owing to their potential for recreational use. The highest prevalence of illegal methamphetamine use occurs in parts of Asia and Oceania, and in the United States, where racemic methamphetamine and dextromethamphetamine are classified as Schedule II controlled substances. Levomethamphetamine is available as an over-the-counter (OTC) drug for use as an inhaled nasal decongestant in the United States.[note 3] Internationally, the production, distribution, sale, and possession of methamphetamine is restricted or banned in many countries, owing to its placement in schedule II of the United Nations Convention on Psychotropic Substances treaty. While dextromethamphetamine is a more potent drug, racemic methamphetamine is illicitly produced more often, owing to the relative ease of synthesis and regulatory limits of chemical precursor availability.

In low to moderate doses, methamphetamine can elevate mood, increase alertness, concentration and energy in fatigued individuals, reduce appetite, and promote weight loss. At very high doses, it can induce psychosis, breakdown of skeletal muscle, seizures, and bleeding in the brain. Chronic high-dose use can precipitate unpredictable and rapid mood swings, stimulant psychosis (e.g., paranoia, hallucinations, delirium, and delusions), and violent behavior. Recreationally, methamphetamine's ability to increase energy has been reported to lift mood and increase sexual desire to such an extent that users are able to engage in sexual activity continuously for several days while binging the drug.[27] Methamphetamine is known to possess a high addiction liability (i.e., a high likelihood that long-term or high dose use will lead to compulsive drug use) and high dependence liability (i.e., a high likelihood that withdrawal symptoms will occur when methamphetamine use ceases). Discontinuing methamphetamine after heavy use may lead to a post-acute-withdrawal syndrome, which can persist for months beyond the typical withdrawal period. At high doses, methamphetamine is neurotoxic to human midbrain dopaminergic neurons and, to a lesser extent, serotonergic neurons.[28][29] Methamphetamine neurotoxicity causes adverse changes in brain structure and function, such as reductions in grey matter volume in several brain regions, as well as adverse changes in markers of metabolic integrity.[29]

Methamphetamine belongs to the substituted phenethylamine and substituted amphetamine chemical classes. It is related to the other dimethylphenethylamines as a positional isomer of these compounds, which share the common chemical formula C10H15N.

Uses

Medical

Desoxyn (methamphetamine hydrochloride) 100 tablets

In the United States, methamphetamine hydrochloride, sold under the brand name Desoxyn, is approved by the FDA for treating ADHD and obesity in both adults and children;[3][30] however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use.[3] To avoid toxicity and risk of side effects, FDA guidelines recommend an initial dose of methamphetamine at doses 5–10 mg/day for ADHD in adults and children over six years of age, and may be increased at weekly intervals of 5 mg, up to 25 mg/day, until optimum clinical response is found; the usual effective dose is around 20–25 mg/day.[23][7][3] Methamphetamine is sometimes prescribed off label for narcolepsy and idiopathic hypersomnia.[31][32] In the United States, methamphetamine's levorotary form is available in some over-the-counter (OTC) nasal decongestant products.[23][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.[3] Methamphetamine hydrochloride dispensed in the United States is required to include a boxed warning regarding its potential for recreational misuse and addiction liability.[3]

Desoxyn and Desoxyn Gradumet are both pharmaceutical forms of the drug. The latter is no longer produced and is a extended-release form of the drug, flattening the curve of the effect of the drug while extending it.[33]

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.[34]

According to a National Geographic TV documentary on methamphetamine, an entire subculture known as party and play is based around sexual activity and methamphetamine use.[34] Participants in this subculture, which consists almost entirely of homosexual male methamphetamine users, will typically meet up through internet dating sites and have sex.[34] Because of its strong stimulant and aphrodisiac effects and inhibitory effect on ejaculation, with repeated use, these sexual encounters will sometimes occur continuously for several days on end.[34] The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia (excessive daytime sleepiness).[34] The party and play subculture is prevalent in major US cities such as San Francisco and New York City.[34][35]

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.[3] The FDA 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.[3] The FDA 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.[3] Owing to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.[3]

Adverse effects

A 2010 study ranking various illegal and legal drugs based on statements by drug-harm experts. Methamphetamine was found to be the fourth most damaging to users.[36]

Physical

Cardiovascular

Methamphetamine is a sympathomimetic drug that causes vasoconstriction and tachycardia. Methamphetamine also promotes abnormal extra heart beats and irregular heart rhythms some of which may be life threatening. [37]

Other physical effects

The effects can also include loss of appetite, hyperactivity, dilated pupils, flushed skin, excessive sweating, increased movement, dry mouth and teeth grinding (potentially leading to condition informally known as meth mouth), headache, rapid breathing, high body temperature, diarrhea, constipation, blurred vision, dizziness, twitching, numbness, tremors, dry skin, acne, and pale appearance.[3][38] Long-term meth users may have sores on their skin;[39][40] these may be caused by scratching due to itchiness or the belief that insects are crawling under their skin,[39] and the damage is compounded by poor diet and hygiene.[40] Numerous deaths related to methamphetamine overdoses have been reported.[41][42] Additionally, "[p]ostmortem examinations of human tissues have linked use of the drug to diseases associated with aging, such as coronary atherosclerosis and pulmonary fibrosis",[43] which may be caused "by a considerable rise in the formation of ceramides, pro-inflammatory molecules that can foster cell aging and death."[43]

Dental and oral health ("meth mouth")

Main article: Meth mouth
A suspected case of meth mouth

Methamphetamine users, particularly heavy users, may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as meth mouth.[44] The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it.[44] 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)".[44][45] As dry mouth is also a common side effect of other stimulants, which are not known to contribute severe tooth decay, many researchers suggest that methamphetamine-associated tooth decay is more due to users' other choices. They suggest the side effect has been exaggerated and stylized to create a stereotype of current users as a deterrence for new ones.[30]

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.[46] 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.[46] 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.[3][47] Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.[3][47]

Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle.[48] The level of needle sharing among methamphetamine users is similar to that among other drug injection users.[48]

Psychological

The psychological effects of methamphetamine can include euphoria, dysphoria, changes in libido, alertness, apprehension and concentration, decreased sense of fatigue, insomnia or wakefulness, self-confidence, sociability, irritability, restlessness, grandiosity and repetitive and obsessive behaviors.[3][38][49] Peculiar to methamphetamine and related stimulants is "punding", persistent non-goal-directed repetitive activity.[50] Methamphetamine use also has a high association with anxiety, depression, amphetamine psychosis, suicide, and violent behaviors.[51][52]

Neurotoxic and neuroimmunological

This diagram depicts the neuroimmune mechanisms that mediate methamphetamine-induced neurodegeneration in the human brain.[53] The NF-κB-mediated neuroimmune response to methamphetamine use which results in the increased permeability of the blood–brain barrier arises through its binding at and activation of sigma receptors, the increased production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and damage-associated molecular pattern molecules (DAMPs), the dysregulation of glutamate transporters (specifically, EAAT1 and EAAT2) and glucose metabolism, and excessive Ca2+ ion influx in glial cells and dopamine neurons.[53][54][55]

Methamphetamine is directly neurotoxic to dopaminergic neurons in both lab animals and humans.[28][29] Excitotoxicity, oxidative stress, metabolic compromise, UPS dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression and other processes contributed to this neurotoxicity.[28][56][4] In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of Parkinson's disease.[57] In addition to its dopaminergic neurotoxicity, a review of evidence in humans indicated that high-dose methamphetamine use can also be neurotoxic to serotonergic neurons.[29] It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.[58] Withdrawal of methamphetamine in dependent persons may lead to post-acute withdrawal which persists months beyond the typical withdrawal period.[4]

Magnetic resonance imaging studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse neuroplastic changes in brain structure and function.[29] In particular, methamphetamine appears to cause hyperintensity and hypertrophy of white matter, marked shrinkage of hippocampi, and reduced gray matter in the cingulate cortex, limbic cortex, and paralimbic cortex in recreational methamphetamine users.[29] Moreover, evidence suggests that adverse changes in the level of biomarkers of metabolic integrity and synthesis occur in recreational users, such as a reduction in N-acetylaspartate and creatine levels and elevated levels of choline and myoinositol.[29]

Methamphetamine has been shown to activate TAAR1 in human astrocytes and generate cAMP as a result.[57] Activation of astrocyte-localized TAAR1 appears to function as a mechanism by which methamphetamine attenuates membrane-bound EAAT2 (SLC1A2) levels and function in these cells.[57]

Methamphetamine binds to and activates both sigma receptor subtypes, σ1 and σ2, with micromolar affinity.[55][59] Sigma receptor activation may promote methamphetamine-induced neurotoxicity by facilitating hyperthermia, increasing dopamine synthesis and release, influencing microglial activation, and modulating apoptotic signaling cascades and the formation of reactive oxygen species.[55][59]

Addictive

Addiction and dependence glossary[60][61][62]
  • addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
  • addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
  • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
  • drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
  • drug withdrawal – symptoms that occur upon cessation of repeated drug use
  • physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
  • psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome)
  • reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
  • rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
  • sensitization – an amplified response to a stimulus resulting from repeated exposure to it
  • substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
  • tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
Signaling cascade in the nucleus accumbens that results in psychostimulant addiction
The image above contains clickable links
This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[63][64] 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.[63][65][66] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[63][67][68] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[69] 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.[67][68] 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.[67][68]


Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.[70][71] The most important transcription factors[note 4] that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB).[71] ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in D1-type medium spiny neurons in the nucleus accumbens is necessary and sufficient[note 5] for most of the behavioral and neural adaptations that arise from addiction.[61][71][73] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[61][73] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[71][73][74][75][76]

ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression).[61][71][77] Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug use (i.e., the alterations mediated by ΔFosB).[71] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[71][74][78] Since both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to produce more of it), chronic acquisition of these rewards can result in a similar pathological state of addiction.[71][74] ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[note 6][74][79] These sex addictions (i.e., drug-induced compulsive sexual behaviors) are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs, such as amphetamine or methamphetamine.[74][78][79]

Epigenetic factors

Methamphetamine addiction is persistent for many individuals, with 61% of individuals treated for addiction relapsing within one year.[80] About half of those with methamphetamine addiction continue with use over a ten-year period, while the other half reduce use starting at about one to four years after initial use.[81]

The frequent persistence of addiction suggests that long-lasting changes in gene expression may occur in particular regions of the brain, and may contribute importantly to the addiction phenotype. In 2014, a crucial role was found for epigenetic mechanisms in driving lasting changes in gene expression in the brain.[77]

A review in 2015[82] summarized a number of studies involving chronic methamphetamine use in rodents. Epigenetic alterations were observed in the brain reward pathways, including areas like ventral tegmental area, nucleus accumbens, and dorsal striatum, the hippocampus, and the prefrontal cortex. Chronic methamphetamine use caused gene-specific histone acetylations, deacetylations and methylations. Gene-specific DNA methylations in particular regions of the brain were also observed. The various epigenetic alterations caused downregulations or upregulations of specific genes important in addiction. For instance, chronic methamphetamine use caused methylation of the lysine in position 4 of histone 3 located at the promoters of the c-fos and the C-C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens (NAc).[82] c-fos is well known to be important in addiction.[83] The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.[82]

In methamphetamine addicted rats, epigenetic regulation through reduced acetylation of histones, in brain striatal neurons, caused reduced transcription of glutamate receptors.[84] Glutamate receptors play an important role in regulating the reinforcing effects of addictive drugs.[85]

Administration of methamphetamine to rodents causes DNA damage in their brain, particularly in the nucleus accumbens region.[86][87] During repair of such DNA damages, persistent chromatin alterations may occur such as in the methylation of DNA or the acetylation or methylation of histones at the sites of repair.[88] These alterations can be epigenetic scars in the chromatin that contribute to the persistent epigenetic changes found in methamphetamine addiction.

Treatment and management

Further information: Addiction § Research

A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).[89] Other treatment modalities examined in the analysis included monotherapy with contingency management or community reinforcement approach, cognitive behavioral therapy, 12-step programs, non-contingent reward-based therapies, psychodynamic therapy, and other combination therapies involving these.[89]

As of December 2019, there is no effective pharmacotherapy for methamphetamine addiction.[90][91][92] A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in randomized controlled trials (RCTs) for amphetamine and methamphetamine addiction;[91] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.[91] There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, mirtazapine, sertraline), antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen, gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.[91][verification needed]

Dependence and withdrawal

Tolerance is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly.[93][94] In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.[95] Depression from methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.[96]

According to the current Cochrane review on drug dependence and withdrawal in recreational users of methamphetamine, "when chronic heavy users abruptly discontinue [methamphetamine] use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose".[95] 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.[95] 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.[95]

Methamphetamine that is present in a mother's bloodstream can pass through the placenta to a fetus and be secreted into breast milk.[96] Infants born to methamphetamine-abusing mothers may experience a neonatal withdrawal syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and hypertonia.[96] This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.[96]

Summary of addiction-related plasticity
Form of neuroplasticity
or behavioral plasticity 		Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
(aerobic) 		Environmental
enrichment
ΔFosB expression in
nucleus accumbens D1-type MSNsTooltip medium spiny neurons 		↑ ↑ ↑ ↑ ↑ ↑ [74]
Behavioral plasticity
Escalation of intake Yes Yes Yes [74]
Psychostimulant
cross-sensitization 		Yes Not applicable Yes Yes Attenuated Attenuated [74]
Psychostimulant
self-administration 		↑ ↑ ↓ ↓ ↓ [74]
Psychostimulant
conditioned place preference 		↑ ↑ ↓ ↑ ↓ ↑ [74]
Reinstatement of drug-seeking behavior ↑ ↑ ↓ ↓ [74]
Neurochemical plasticity
CREBTooltip cAMP response element-binding protein phosphorylation
in the nucleus accumbens 		↓ ↓ ↓ ↓ ↓ [74]
Sensitized dopamine response
in the nucleus accumbens 		No Yes No Yes [74]
Altered striatal dopamine signaling ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD2 ↑DRD2 [74]
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 [74]
Changes in striatal opioid peptides ↑dynorphin
No change: enkephalin		 ↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin [74]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens ↓ ↑ ↑ [74]
Dendritic spine density in
the nucleus accumbens 		↓ ↑ ↑ [74]

Neonatal

Unlike other drugs, babies with prenatal exposure to methamphetamine do not show immediate signs of withdrawal. Instead, cognitive and behavioral problems start emerging when the children reach school age.[97]

A prospective cohort study of 330 children showed that at the age of 3, children with methamphetamine exposure showed increased emotional reactivity, as well as more signs of anxiety and depression; and at the age of 5, children showed higher rates of externalizing and attention deficit/hyperactivity disorders.[98]

Overdose

Methamphetamine overdose is a diverse term. It frequently refers to the exaggeration of the unusual effects with features such as irritability, agitation, hallucinations and paranoia.[5][3] The cardiovascular effects are typically not noticed in young healthy people. Hypertension and tachycardia are not apparent unless measured. 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.[5][38] An extremely large overdose may produce symptoms such as adrenergic storm, methamphetamine psychosis, substantially reduced or no urine output, cardiogenic shock, bleeding in the brain, circulatory collapse, hyperpy rexia (i.e., dangerously high body temperature), pulmonary hypertension, kidney failure, rapid muscle breakdown, serotonin syndrome, and a form of stereotypy ("tweaking").[sources 1] A methamphetamine overdose will likely also result in mild brain damage owing to dopaminergic and serotonergic neurotoxicity.[102][29] Death from methamphetamine poisoning is typically preceded by convulsions and coma.[3]

Psychosis

Main section: Stimulant psychosis § Substituted amphetamines

Use of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g., paranoia, hallucinations, delirium, and delusions).[5][103] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine use-induced psychosis states that about 5–15% of users fail to recover completely.[103][104] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[103] Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[105]

Death from overdose

The CDC reported that the number of deaths in the United States involving psychostimulants with abuse potential to be 23,837 in 2020 and 32,537 in 2021.[106] This category code (ICD–10 of T43.6) includes primarily methamphetamine but also other stimulants such as amphetamine, and methylphenidate. The mechanism of death in these cases is not reported in these statistics and is difficult to know.[107] Unlike fentanyl which causes respiratory depression, methamphetamine is not a respiratory depressant. Some deaths are as a result of intracranial hemorrhage[108] and some deaths are cardiovascular in nature including flash pulmonary edema[109] and ventricular fibrillation.[110][111]

Emergency treatment

Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of activated charcoal and sedation.[5] There is not enough evidence on hemodialysis or peritoneal dialysis in cases of methamphetamine intoxication to determine their usefulness.[3] 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.[5] Hypertension presents a risk for intracranial hemorrhage (i.e., bleeding in the brain) and, if severe, is typically treated with intravenous phentolamine or nitroprusside.[5] Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment.[5]

Antipsychotics such as haloperidol are useful in treating agitation and psychosis from methamphetamine overdose.[112][113] Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity.[114][failed verification] The mixed alpha- and beta-blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.[112] The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.[112]

Interactions

Methamphetamine is metabolized by the liver enzyme CYP2D6, so CYP2D6 inhibitors will prolong the elimination half-life of methamphetamine.[3][115] Methamphetamine also interacts with monoamine oxidase inhibitors (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.[3] Methamphetamine may decrease the effects of sedatives and depressants and increase the effects of antidepressants and other stimulants as well.[3] Methamphetamine may counteract the effects of antihypertensives and antipsychotics owing to its effects on the cardiovascular system and cognition respectively.[3] The pH of gastrointestinal content and urine affects the absorption and excretion of methamphetamine.[3] Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite.[3] Owing to the effect pH has on absorption, proton pump inhibitors, which reduce gastric acid, are known to interact with methamphetamine.[3]

Pharmacology

An image of methamphetamine pharmacodynamics
This illustration depicts the normal operation of the dopaminergic terminal to the left, and the dopaminergic terminal in the 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).

Pharmacodynamics

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.[116][117] Activation of TAAR1 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).[116][118] 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.[116][119] Methamphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent signaling pathway, in turn producing dopamine efflux.[120][121][122] TAAR1 has been shown to reduce the firing rate of neurons through direct activation of G protein-coupled inwardly-rectifying potassium channels.[123][124][125] TAAR1 activation by methamphetamine in astrocytes appears to negatively modulate the membrane expression and function of EAAT2, a type of glutamate transporter.[57]

In addition to its effect on the plasma membrane monoamine transporters, methamphetamine inhibits synaptic vesicle function by inhibiting VMAT2, which prevents monoamine uptake into the vesicles and promotes their release.[126] This results in the outflow of monoamines from synaptic vesicles into the cytosol (intracellular fluid) of the presynaptic neuron, and their subsequent release into the synaptic cleft by the phosphorylated transporters.[127] Other transporters that methamphetamine is known to inhibit are SLC22A3 and SLC22A5.[126] SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.[117][128]

Methamphetamine is also an agonist of the alpha-2 adrenergic receptors and sigma receptors with a greater affinity for σ1 than σ2, and inhibits monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B).[55][117][59] Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain.[55][59] Dextromethamphetamine is a stronger psychostimulant, but levomethamphetamine has stronger peripheral effects, a longer half-life, and longer perceived effects among heavy substance users.[129][130][131] At high doses, both enantiomers of methamphetamine can induce similar stereotypy and methamphetamine psychosis,[130] but levomethamphetamine has shorter psychodynamic effects.[131]

Pharmacokinetics

The bioavailability of methamphetamine is 67% orally, 79% intranasally, 67 to 90% via inhalation (smoking), and 100% intravenously.[4][5][6] 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.[132] Methamphetamine is also well absorbed following inhalation and following intranasal administration.[5] Because of the high lipophilicity of methamphetamine due to its methyl group, it can readily move through the blood–brain barrier faster than other stimulants, where it is more resistant to degradation by monoamine oxidase.[5][132][133] The amphetamine metabolite peaks at 10–24 hours.[5] Methamphetamine is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH.[3][132] When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine.[132] Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine.[132] The elimination half-life of methamphetamine varies with a range of 5–30 hours, but it is on average 9 to 12 hours in most studies.[5][4] The elimination half-life of methamphetamine does not vary by route of administration, but is subject to substantial interindividual variability.[4]

CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase 3, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize methamphetamine or its metabolites in humans.[sources 2] The primary metabolites are amphetamine and 4-hydroxymethamphetamine;[132] other minor metabolites include: 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone, the metabolites of amphetamine.[10][132][134] Among these metabolites, the active sympathomimetics are amphetamine, 4‑hydroxyamphetamine,[140] 4‑hydroxynorephedrine,[141] 4-hydroxymethamphetamine,[132] and norephedrine.[142] Methamphetamine is a CYP2D6 inhibitor.[115]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[10][132][143] The known metabolic pathways include:

Metabolic pathways of methamphetamine in humans[sources 2]
The image above contains clickable links
The primary metabolites of methamphetamine are amphetamine and 4-hydroxymethamphetamine.[132] Human microbiota, particularly Lactobacillus, Enterococcus, and Clostridium species, contribute to the metabolism of methamphetamine via an enzyme which N-demethylates methamphetamine and 4-hydroxymethamphetamine into amphetamine and 4-hydroxyamphetamine respectively.[144][145]

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.[146][147][148][149] Chiral techniques may be employed to help distinguish the source of the drug to determine whether it was obtained illicitly or legally via prescription or prodrug.[150] Chiral separation is needed to assess the possible contribution of levomethamphetamine, which is an active ingredients in some OTC nasal decongestants,[note 3] toward a positive test result.[150][151][152] Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.[153]

Chemistry

Shards of pure 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.[13] It is soluble in diethyl ether and ethanol as well as miscible with chloroform.[13]

In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste.[13] It has a melting point between 170 and 175 °C (338 and 347 °F) and, at room temperature, occurs as white crystals or a white crystalline powder.[13] The hydrochloride salt is also freely soluble in ethanol and water.[13] The crystal structure of either enantiomer is monoclinic with P21 space group; at 90 K (−183.2 °C; −297.7 °F), it has lattice parameters a = 7.10 Å, b = 7.29 Å, c = 10.81 Å, and β = 97.29°.[154]

Degradation

A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration.[155] A year-long study (also from 2011) showed that methamphetamine in soils is a persistent pollutant.[156] In a 2013 study of bioreactors in wastewater, methamphetamine was found to be largely degraded within 30 days under exposure to light.[157]

Synthesis

Further information on illicit amphetamine synthesis: History and culture of substituted amphetamines § Illegal synthesis

Racemic methamphetamine may be prepared starting from phenylacetone by either the Leuckart[158] or reductive amination methods.[159] 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.[159] In this reaction, an iminium cation is formed as an intermediate which is reduced by the second equivalent of N-methylformamide.[159] The intermediate formyl amide is then hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product.[159] Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.[159]

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

History, society, and culture

Main article: History and culture of substituted amphetamines
A methamphetamine tablet container
Pervitin, a methamphetamine brand used by German soldiers during World War II, was dispensed in these tablet containers.
U.S. drug overdose related fatalities in 2017 were 70,200, including 10,333 of those related to psychostimulants (including methamphetamine).[160][161]

Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine.[162][163] Shortly after, methamphetamine was synthesized from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi.[164] Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.[165]

From 1938, methamphetamine was marketed on a large scale in Germany as a nonprescription drug under the brand name Pervitin, produced by the Berlin-based Temmler pharmaceutical company.[166][167] It was used by all branches of the combined armed forces of the Third Reich, for its stimulant effects and to induce extended wakefulness.[168][169] Pervitin became colloquially known among the German troops as "Stuka-Tablets" (Stuka-Tabletten) and "Herman-Göring-Pills" (Hermann-Göring-Pillen), as a snide allusion to Göring's widely-known addiction to drugs. However, the side effects, particularly the withdrawal symptoms, were so serious that the army sharply cut back its usage in 1940.[170] By 1941, usage was restricted to a doctor's prescription, and the military tightly controlled its distribution. Soldiers would only receive a couple of tablets at a time, and were discouraged from using them in combat. Historian Łukasz Kamieński says,

A soldier going to battle on Pervitin usually found himself unable to perform effectively for the next day or two. Suffering from a drug hangover and looking more like a zombie than a great warrior, he had to recover from the side effects.

Some soldiers turned violent, committing war crimes against civilians; others attacked their own officers.[170] At the end of the war, it was used as part of a new drug: D-IX.

Obetrol, patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of obesity, was one of the first brands of pharmaceutical methamphetamine products.[171] Because of the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s.[171] Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.[163] For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act.[172] Currently, methamphetamine is sold under the trade name Desoxyn, trademarked by the Danish pharmaceutical company Lundbeck.[173] As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.[174]

Trafficking

The Golden Triangle (Southeast Asia), specifically Shan State, Myanmar, is the world's leading producer of methamphetamine as production has shifted to Yaba and crystalline methamphetamine, including for export to the United States and across East and Southeast Asia and the Pacific.[175]

Concerning the accelerating synthetic drug production in the region, the Cantonese Chinese syndicate Sam Gor, also known as The Company, is understood to be the main international crime syndicate responsible for this shift.[176] It is made up of members of five different triads. Sam Gor is primarily involved in drug trafficking, earning at least $8 billion per year.[177] Sam Gor is alleged to control 40% of the Asia-Pacific methamphetamine market, while also trafficking heroin and ketamine. The organization is active in a variety of countries, including Myanmar, Thailand, New Zealand, Australia, Japan, China, and Taiwan. Sam Gor previously produced meth in Southern China and is now believed to manufacture mainly in the Golden Triangle, specifically Shan State, Myanmar, responsible for much of the massive surge of crystal meth in circa 2019.[178] The group is understood to be headed by Tse Chi Lop, a gangster born in Guangzhou, China who also holds a Canadian passport.

Liu Zhaohua was another individual involved in the production and trafficking of methamphetamine until his arrest in 2005.[179] It was estimated over 18 tonnes of methamphetamine were produced under his watch.[179]

Main article: Legal status of methamphetamine

The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions.[180][181] In some jurisdictions, it is legally available as a prescription medication. Methamphetamine has been placed in schedule II of the United Nations Convention on Psychotropic Substances treaty, indicating that it has limited medical use.[181]

Research

Animal models have shown that low-dose methamphetamine improves cognitive and behavioural functioning following TBI (traumatic brain injury).[7] This is in contrast to high, repeated doses which cause neurotoxicity. These models demonstrate that low-dose methamphetamine increases neurogenesis and reduces apoptosis in the dentate gyrus of the hippocampus following TBI.[182] It has also been found that TBI patients testing positive for methamphetamine at the time of emergency department admission have lower rates of mortality.[183]

It has been suggested, based on animal research, that calcitriol, the active metabolite of vitamin D, can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of methamphetamine.[184] Protection against methamphetamine-induced neurotoxicity has also been observed following administration of ascorbic acid (vitamin C),[185] cobalamin (vitamin B12),[186] and vitamin E.[187]

See also

Footnotes

  1. ^
      Ion channel
      G proteins & linked receptors
      (Text color) Transcription factors
  1. ^ Synonyms and alternate spellings include: N-methylamphetamine, desoxyephedrine, Syndrox, Methedrine, and Desoxyn.[14][15][16] Common slang terms for methamphetamine include: meth, speed, crank and shabu (also sabu and shabu-shabu) in Indonesia and the Philippines,[17][18][19][20] and for the hydrochloride crystal, crystal meth, glass, shards, and ice,[21] and, in New Zealand, P.[22]
  2. ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.
    Levomethamphetamine and dextromethamphetamine are also known as L-methamphetamine, (R)-methamphetamine, or levmetamfetamine (International Nonproprietary Name [INN]) and D-methamphetamine, (S)-methamphetamine, or metamfetamine (INN), respectively.[14][24]
  3. ^ a b c The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[25][26]
  4. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[72]
  5. ^ In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.
  6. ^ The associated research only involved amphetamine, not methamphetamine; however, this statement is included here due to the similarity between the pharmacodynamics and aphrodisiac effects of amphetamine and methamphetamine.

Reference notes

  1. ^ [5][3][38][49][99][100][101]
  2. ^ a b [9][10][11][12][132][134][135][136][137][138][139]

References

  1. ^ "methamphetamine". Methamphetamine. Lexico. Archived from the original on 14 June 2021. Retrieved 22 April 2022.
  2. ^ Anvisa (24 July 2023). "RDC Nº 804 – Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 – Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 25 July 2023). Archived from the original on 27 August 2023. Retrieved 27 August 2023.
  3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z "Desoxyn- methamphetamine hydrochloride tablet". DailyMed. 8 September 2022. Archived from the original on 22 September 2024. Retrieved 20 June 2024.
  4. ^ a b c d e f g h i j k l m n Cruickshank CC, Dyer KR (July 2009). "A review of the clinical pharmacology of methamphetamine". Addiction (Abingdon, England). 104 (7): 1085–1099. doi:10.1111/j.1360-0443.2009.02564.x. PMID 19426289. S2CID 37079117.
  5. ^ a b c d e f g h i j k l m n o p q r Schep LJ, Slaughter RJ, Beasley DM (August 2010). "The clinical toxicology of metamfetamine". Clinical Toxicology. 48 (7): 675–694. doi:10.3109/15563650.2010.516752. ISSN 1556-3650. PMID 20849327. S2CID 42588722.
  6. ^ a b c d Courtney KE, Ray LA (October 2014). "Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature". Drug Alcohol Depend. 143: 11–21. doi:10.1016/j.drugalcdep.2014.08.003. PMC 4164186. PMID 25176528.
  7. ^ a b c d e Rau T, Ziemniak J, Poulsen D (January 2016). "The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury". Progress in Neuro-psychopharmacology & Biological Psychiatry. 64: 231–236. doi:10.1016/j.pnpbp.2015.02.013. ISSN 0278-5846. PMID 25724762.
  8. ^ "Methamphetamine: Toxicity". PubChem Compound. National Center for Biotechnology Information. Archived from the original on 4 January 2015. Retrieved 4 January 2015.
  9. ^ a b Sellers EM, Tyndale RF (2000). "Mimicking gene defects to treat drug dependence". Ann. N. Y. Acad. Sci. 909 (1): 233–246. Bibcode:2000NYASA.909..233S. doi:10.1111/j.1749-6632.2000.tb06685.x. PMID 10911933. S2CID 27787938. Methamphetamine, a central nervous system stimulant drug, is p-hydroxylated by CYP2D6 to less active p-OH-methamphetamine.
  10. ^ a b c d "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Archived (PDF) from the original on 30 December 2013. Retrieved 30 December 2013.
  11. ^ a b 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.
    Krueger SK, Williams DE (2005). "Table 5: N-containing drugs and xenobiotics oxygenated by FMO". Pharmacology & Therapeutics. 106 (3): 357–387. doi:10.1016/j.pharmthera.2005.01.001. PMC 1828602. PMID 15922018. Archived from the original on 16 September 2018.
  12. ^ a b Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication". J. Pharmacol. Exp. Ther. 288 (3): 1251–1260. PMID 10027866.
  13. ^ a b c d e f g "Methamphetamine: Chemical and Physical Properties". PubChem Compound. National Center for Biotechnology Information. Archived from the original on 4 January 2015. Retrieved 4 January 2015.
  14. ^ a b "Methamphetamine". Drug profiles. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). 8 January 2015. Archived from the original on 15 April 2016. Retrieved 27 November 2018. The term metamfetamine (the International Non-Proprietary Name: INN) strictly relates to the specific enantiomer (S)-N,α-dimethylbenzeneethanamine.
  15. ^ "Methamphetamine: Identification". DrugBank. University of Alberta. 8 February 2013. Archived from the original on 28 December 2015. Retrieved 1 January 2014.
  16. ^ "Methedrine (methamphetamine hydrochloride): Uses, Symptoms, Signs and Addiction Treatment". Addictionlibrary.org. Archived from the original on 4 March 2016. Retrieved 16 January 2016.
  17. ^ "Polisi Tangkap Bandar Shabu-shabu". Detik News (in Indonesian). Archived from the original on 29 July 2023. Retrieved 29 July 2023.
  18. ^ "P1-M shabu seized from 3 drug pushers". Manila Bulletin. Retrieved 29 July 2023.
  19. ^ "Jadi pengedar sabu seorang IRT di Pidoli Dolok ditangkap Polisi – ANTARA News Sumatera Utara". ANTARA News Agency. Archived from the original on 22 September 2024. Retrieved 29 July 2023.
  20. ^ Marantal RD. "E-bike driver nabbed in drug bust, shabu worth almost P1 million seized". Philstar.com. Archived from the original on 29 July 2023. Retrieved 29 July 2023.
  21. ^ "Meth Slang Names". MethhelpOnline. Archived from the original on 7 December 2013. Retrieved 1 January 2014.
  22. ^ "Methamphetamine and the law". Archived from the original on 28 January 2015. Retrieved 30 December 2014.
  23. ^ a b c d e Moszczynska A, Callan SP (September 2017). "Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment". The Journal of Pharmacology and Experimental Therapeutics. 362 (3): 474–488. doi:10.1124/jpet.116.238501. PMC 11047030. PMID 28630283. METH is a schedule II drug, which can only be prescribed for attention deficit hyperactivity disorder (ADHD), extreme obesity, or narcolepsy (as Desoxyn; Recordati Rare Diseases LLC, Lebanon, NJ), with amphetamine being prescribed more often for these conditions due to amphetamine having lower reinforcing potential than METH (Lile et al., 2013). ...
    As discussed earlier, the d-enantiomer has stronger CNS effects but is metabolized more quickly than the l-enantiomer, which is longer lasting due to the slower breakdown. ...
    l-METH, a vasoconstrictor, is the active constituent of the Vicks Inhaler decongestant (Proctor & Gamble, Cincinnati, OH), an over-the-counter product containing about 50 mg of the drug (Smith et al., 2014). Desoxyn, which is d-METH, is rarely medically prescribed due to its strong reinforcing properties. Therapeutic doses of Desoxyn are 20–25 mg daily, taken every 12 hours, with dosing not exceeding 60 mg/day
  24. ^ "Levomethamphetamine". Pubchem Compound. National Center for Biotechnology Information. Archived from the original on 6 October 2014. Retrieved 27 November 2018.
  25. ^ "Code of Federal Regulations Title 21: Subchapter D – Drugs for human use, Part 341 – cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use". United States Food and Drug Administration. April 2015. Archived from the original on 25 December 2019. Retrieved 7 March 2016. 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 every 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.
  26. ^ "Levomethamphetamine: Identification". Pubchem Compound. National Center for Biotechnology Information. Archived from the original on 6 October 2014. Retrieved 4 September 2017.
  27. ^ "Meth's aphrodisiac effect adds to drug's allure". NBC News. Associated Press. 3 December 2004. Archived from the original on 12 August 2013. Retrieved 12 September 2019.
  28. ^ a b c Yu S, Zhu L, Shen Q, Bai X, Di X (March 2015). "Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology". Behavioural Neurology. 2015 (103969): 1–11. doi:10.1155/2015/103969. PMC 4377385. PMID 25861156.
  29. ^ a b c d e f g h 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).
  30. ^ a b 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.
  31. ^ Mitler MM, Hajdukovic R, Erman MK (1993). "Treatment of narcolepsy with methamphetamine". Sleep. 16 (4): 306–317. PMC 2267865. PMID 8341891.
  32. ^ Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, et al. (2007). "Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin". Sleep. 30 (12): 1705–11. doi:10.1093/sleep/30.12.1705. PMC 2276123. PMID 18246980.
  33. ^ "Desoxyn Gradumet Side Effects". Drugs.com. 19 March 2022. Archived from the original on 18 October 2022. Retrieved 18 October 2022.
  34. ^ a b c d e f San Francisco Meth Zombies (TV documentary). National Geographic Channel. August 2013. ASIN B00EHAOBAO. Archived from the original on 8 July 2016. Retrieved 7 July 2016.
  35. ^ Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE (2011). Goldfrank's toxicologic emergencies (9th ed.). New York: McGraw-Hill Medical. p. 1080. ISBN 978-0-07-160593-9.
  36. ^ Nutt DJ, King LA, Phillips LD (November 2010). "Drug harms in the UK: a multicriteria decision analysis". Lancet. 376 (9752): 1558–65. CiteSeerX 10.1.1.690.1283. doi:10.1016/S0140-6736(10)61462-6. PMID 21036393. S2CID 5667719.
  37. ^ Kevil CG, Goeders NE, Woolard MD, Bhuiyan MS, Dominic P, Kolluru GK, et al. (September 2019). "Methamphetamine Use and Cardiovascular Disease". Arteriosclerosis, Thrombosis, and Vascular Biology. 39 (9): 1739–1746. doi:10.1161/ATVBAHA.119.312461. PMC 6709697. PMID 31433698.
  38. ^ a b c d Westfall DP, Westfall TC (2010). "Miscellaneous Sympathomimetic Agonists". In Brunton LL, Chabner BA, Knollmann BC (eds.). Goodman & Gilman's Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. ISBN 978-0-07-162442-8. Archived from the original on 10 November 2013. Retrieved 1 January 2014.
  39. ^ a b "What are the long-term effects of methamphetamine misuse?". National Institute on Drug Abuse. National Institutes of Health, U.S. Department of Health & Human Services. October 2019. Archived from the original on 29 March 2020. Retrieved 15 March 2020.
  40. ^ a b Elkins C (27 February 2020). "Meth Sores". DrugRehab.com. Advanced Recovery Systems. Archived from the original on 14 August 2020. Retrieved 15 March 2020.
  41. ^ "Meth Overdose Symptoms, Effects & Treatment | BlueCrest". Bluecrest Recovery Center. 17 June 2019. Archived from the original on 16 January 2021. Retrieved 8 October 2020.
  42. ^ National Institute on Drug Abuse (29 January 2021). "Overdose Death Rates". National Institute on Drug Abuse. Archived from the original on 25 January 2018. Retrieved 8 October 2020.
  43. ^ a b "Accelerated cellular aging caused by methamphetamine use limited in lab". ScienceDaily. 11 February 2015. Archived from the original on 22 September 2024. Retrieved 29 July 2024.
  44. ^ a b c 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.
  45. ^ "Methamphetamine Use (Meth Mouth)". American Dental Association. Archived from the original on 1 June 2008. Retrieved 15 December 2006.
  46. ^ a b 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. PMC 4669892. PMID 18661225.
  47. ^ a b Moore P (June 2005). "We Are Not OK". VillageVoice. Archived from the original on 4 June 2011. Retrieved 15 January 2011.
  48. ^ a b "Methamphetamine Use and Health | UNSW: The University of New South Wales – Faculty of Medicine" (PDF). Archived from the original (PDF) on 16 August 2008. Retrieved 15 January 2011.
  49. ^ a b O'Connor PG (February 2012). "Amphetamines". Merck Manual for Health Care Professionals. Merck. Archived from the original on 6 May 2012. Retrieved 8 May 2012.
  50. ^ Rusinyak DE (2011). "Neurologic manifestations of chronic methamphetamine abuse". Neurologic Clinics. 29 (3): 641–655. doi:10.1016/j.ncl.2011.05.004. PMC 3148451. PMID 21803215.
  51. ^ 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.
  52. ^ Raskin S (26 December 2021). "Missouri sword slay suspect smiles for mug shot after allegedly killing beau". New York Post. Archived from the original on 26 December 2021. Retrieved 26 December 2021.
  53. ^ a b Beardsley PM, Hauser KF (2014). "Glial Modulators as Potential Treatments of Psychostimulant Abuse". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Advances in Pharmacology. Vol. 69. Academic Press. pp. 1–69. doi:10.1016/B978-0-12-420118-7.00001-9. ISBN 978-0-12-420118-7. PMC 4103010. PMID 24484974. Glia (including astrocytes, microglia, and oligodendrocytes), which constitute the majority of cells in the brain, have many of the same receptors as neurons, secrete neurotransmitters and neurotrophic and neuroinflammatory factors, control clearance of neurotransmitters from synaptic clefts, and are intimately involved in synaptic plasticity. Despite their prevalence and spectrum of functions, appreciation of their potential general importance has been elusive since their identification in the mid-1800s, and only relatively recently have they been gaining their due respect. This development of appreciation has been nurtured by the growing awareness that drugs of abuse, including the psychostimulants, affect glial activity, and glial activity, in turn, has been found to modulate the effects of the psychostimulants
  54. ^ Loftis JM, Janowsky A (2014). "Neuroimmune basis of methamphetamine toxicity". Neuroimmune Signaling in Drug Actions and Addictions. International Review of Neurobiology. Vol. 118. Academic Press. pp. 165–197. doi:10.1016/B978-0-12-801284-0.00007-5. ISBN 978-0-12-801284-0. PMC 4418472. PMID 25175865. Collectively, these pathological processes contribute to neurotoxicity (e.g., increased BBB permeability, inflammation, neuronal degeneration, cell death) and neuropsychiatric impairments (e.g., cognitive deficits, mood disorders)
    Loftis JM, Janowsky A (2014). "Figure 7.1: Neuroimmune mechanisms of methamphetamine-induced CNS toxicity". International Review of Neurobiology. 118: 165–197. doi:10.1016/B978-0-12-801284-0.00007-5. PMC 4418472. PMID 25175865."
  55. ^ a b c d e Kaushal N, Matsumoto RR (March 2011). "Role of sigma receptors in methamphetamine-induced neurotoxicity". Curr Neuropharmacol. 9 (1): 54–57. doi:10.2174/157015911795016930. PMC 3137201. PMID 21886562. σ Receptors seem to play an important role in many of the effects of METH. They are present in the organs that mediate the actions of METH (e.g. brain, heart, lungs) [5]. In the brain, METH acts primarily on the dopaminergic system to cause acute locomotor stimulant, subchronic sensitized, and neurotoxic effects. σ Receptors are present on dopaminergic neurons and their activation stimulates dopamine synthesis and release [11–13]. σ-2 Receptors modulate DAT and the release of dopamine via protein kinase C (PKC) and Ca2+-calmodulin systems [14].
    σ-1 Receptor antisense and antagonists have been shown to block the acute locomotor stimulant effects of METH [4]. Repeated administration or self administration of METH has been shown to upregulate σ-1 receptor protein and mRNA in various brain regions including the substantia nigra, frontal cortex, cerebellum, midbrain, and hippocampus [15, 16]. Additionally, σ receptor antagonists ... prevent the development of behavioral sensitization to METH [17, 18]. ...
    σ Receptor agonists have been shown to facilitate dopamine release, through both σ-1 and σ-2 receptors [11–14].
  56. ^ Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, et al. (August 2012). "Toxicity of amphetamines: an update". Arch. Toxicol. 86 (8): 1167–1231. Bibcode:2012ArTox..86.1167C. doi:10.1007/s00204-012-0815-5. PMID 22392347. S2CID 2873101.
  57. ^ a b c d  • Cisneros IE, Ghorpade A (October 2014). "Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes". Neuropharmacology. 85: 499–507. doi:10.1016/j.neuropharm.2014.06.011. PMC 4315503. PMID 24950453. TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance ... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function.
     • Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMC 4532615. PMID 26092759. TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007)
  58. ^ 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. S2CID 11909155.
  59. ^ a b c d Rodvelt KR, Miller DK (September 2010). "Could sigma receptor ligands be a treatment for methamphetamine addiction?". Curr Drug Abuse Rev. 3 (3): 156–162. doi:10.2174/1874473711003030156. PMID 21054260.
  60. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. ISBN 9780071481274.
  61. ^ a b c d Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
  62. ^ Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC 6135257. PMID 26816013. 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.
  63. ^ a b c Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
    Figure 2: Psychostimulant-induced signaling events
  64. ^ Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC 3250102. PMID 22200950. Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
  65. ^ 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.
  66. ^ 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". Molecular Neurobiology. 51 (2): 696–717 (Figure 1). doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.
  67. ^ a b c Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 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
  68. ^ a b c Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 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
  69. ^ Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 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
  70. ^ Hyman SE, Malenka RC, Nestler EJ (July 2006). "Neural mechanisms of addiction: the role of reward-related learning and memory" (PDF). Annu. Rev. Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. S2CID 15139406. Archived from the original (PDF) on 19 September 2018.
  71. ^ a b c d e f g h 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.
  72. ^ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 4: Signal Transduction in the Brain". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 94. ISBN 978-0-07-148127-4.
  73. ^ a b c Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
  74. ^ a b c d e f g h i j k l m n o p q r Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. 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).
  75. ^ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Archived from the original on 13 October 2014. Retrieved 31 October 2014.
  76. ^ Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proc. Natl. Acad. Sci. U.S.A. 106 (8): 2915–2920. Bibcode:2009PNAS..106.2915K. doi:10.1073/pnas.0813179106. PMC 2650365. PMID 19202072.
  77. ^ a b Nestler EJ (January 2014). "Epigenetic mechanisms of drug addiction". Neuropharmacology. 76 (Pt B): 259–268. doi:10.1016/j.neuropharm.2013.04.004. PMC 3766384. PMID 23643695.
  78. ^ a b Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, et al. (March 2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of 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.
  79. ^ a b 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. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... 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. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity
  80. ^ Brecht ML, Herbeck D (June 2014). "Time to relapse following treatment for methamphetamine use: a long-term perspective on patterns and predictors". Drug Alcohol Depend. 139: 18–25. doi:10.1016/j.drugalcdep.2014.02.702. PMC 4550209. PMID 24685563.
  81. ^ Brecht ML, Lovinger K, Herbeck DM, Urada D (2013). "Patterns of treatment utilization and methamphetamine use during first 10 years after methamphetamine initiation". J Subst Abuse Treat. 44 (5): 548–56. doi:10.1016/j.jsat.2012.12.006. PMC 3602162. PMID 23313146.
  82. ^ a b c Godino A, Jayanthi S, Cadet JL (2015). "Epigenetic landscape of amphetamine and methamphetamine addiction in rodents". Epigenetics. 10 (7): 574–80. doi:10.1080/15592294.2015.1055441. PMC 4622560. PMID 26023847.
  83. ^ Cruz FC, Javier Rubio F, Hope BT (December 2015). "Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction". Brain Res. 1628 (Pt A): 157–73. doi:10.1016/j.brainres.2014.11.005. PMC 4427550. PMID 25446457.
  84. ^ Jayanthi S, McCoy MT, Chen B, Britt JP, Kourrich S, Yau HJ, et al. (July 2014). "Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms". Biol. Psychiatry. 76 (1): 47–56. doi:10.1016/j.biopsych.2013.09.034. PMC 3989474. PMID 24239129.
  85. ^ Kenny PJ, Markou A (May 2004). "The ups and downs of addiction: role of metabotropic glutamate receptors". Trends Pharmacol. Sci. 25 (5): 265–72. doi:10.1016/j.tips.2004.03.009. PMID 15120493.
  86. ^ Tokunaga I, Ishigami A, Kubo S, Gotohda T, Kitamura O (August 2008). "The peroxidative DNA damage and apoptosis in methamphetamine-treated rat brain". The Journal of Medical Investigation. 55 (3–4): 241–245. doi:10.2152/jmi.55.241. PMID 18797138.
  87. ^ Johnson Z, Venters J, Guarraci FA, Zewail-Foote M (June 2015). "Methamphetamine induces DNA damage in specific regions of the female rat brain". Clinical and Experimental Pharmacology & Physiology. 42 (6): 570–575. doi:10.1111/1440-1681.12404. PMID 25867833. S2CID 24182756.
  88. ^ Dabin J, Fortuny A, Polo SE (June 2016). "Epigenome Maintenance in Response to DNA Damage". Molecular Cell. 62 (5): 712–727. doi:10.1016/j.molcel.2016.04.006. PMC 5476208. PMID 27259203.
  89. ^ a b De Crescenzo F, Ciabattini M, D'Alò GL, De Giorgi R, Del Giovane C, Cassar C, et al. (December 2018). "Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis". PLOS Medicine. 15 (12): e1002715. doi:10.1371/journal.pmed.1002715. PMC 6306153. PMID 30586362.
  90. ^ Stoops WW, Rush CR (May 2014). "Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research". Expert Rev Clin Pharmacol. 7 (3): 363–374. doi:10.1586/17512433.2014.909283. PMC 4017926. PMID 24716825. Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.
  91. ^ a b c d Chan B, Freeman M, Kondo K, Ayers C, Montgomery J, Paynter R, et al. (December 2019). "Pharmacotherapy for methamphetamine/amphetamine use disorder-a systematic review and meta-analysis". Addiction. 114 (12): 2122–2136. doi:10.1111/add.14755. PMID 31328345. S2CID 198136436.
  92. ^ Forray A, Sofuoglu M (February 2014). "Future pharmacological treatments for substance use disorders". Br. J. Clin. Pharmacol. 77 (2): 382–400. doi:10.1111/j.1365-2125.2012.04474.x. PMC 4014020. PMID 23039267.
  93. ^ O'Connor P. "Amphetamines: Drug Use and Abuse". Merck Manual Home Health Handbook. Merck. Archived from the original on 17 February 2007. Retrieved 26 September 2013.
  94. ^ Pérez-Mañá C, Castells X, Torrens M, Capellà D, Farre M (2013). Pérez-Mañá C (ed.). "Efficacy of psychostimulant drugs for amphetamine abuse or dependence". Cochrane Database Syst. Rev. 2013 (9): CD009695. doi:10.1002/14651858.CD009695.pub2. PMC 11521360. PMID 23996457.
  95. ^ a b c d Shoptaw SJ, Kao U, Heinzerling K, Ling W (2009). Shoptaw SJ (ed.). "Treatment for amphetamine withdrawal". Cochrane Database Syst. Rev. 2009 (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMC 7138250. 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)
  96. ^ a b c d Winslow BT, Voorhees KI, Pehl KA (2007). "Methamphetamine abuse". American Family Physician. 76 (8): 1169–1174. PMID 17990840.
  97. ^ Kennedy E (3 January 2020). "Babies born to meth-affected mothers seem well behaved, but their passive nature masks a serious problem". ABC News Online. Archived from the original on 24 October 2021.
  98. ^ LaGasse LL, Derauf C, Smith LM, Newman E, Shah R, Neal C, et al. (April 2012). "Prenatal methamphetamine exposure and childhood behavior problems at 3 and 5 years of age". Pediatrics. 129 (4). American Academy of Pediatrics: 681–8. doi:10.1542/peds.2011-2209. PMC 3313637. PMID 22430455.
  99. ^ Albertson TE (2011). "Amphetamines". In Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AH (eds.). Poisoning & Drug Overdose (6th ed.). New York: McGraw-Hill Medical. pp. 77–79. ISBN 978-0-07-166833-0.
  100. ^ Oskie SM, Rhee JW (11 February 2011). "Amphetamine Poisoning". Emergency Central. Unbound Medicine. Archived from the original on 26 September 2013. Retrieved 11 June 2013.
  101. ^ Isbister GK, Buckley NA, Whyte IM (September 2007). "Serotonin toxicity: a practical approach to diagnosis and treatment" (PDF). Med. J. Aust. 187 (6): 361–365. doi:10.5694/j.1326-5377.2007.tb01282.x. PMID 17874986. S2CID 13108173. Archived (PDF) from the original on 4 July 2014. Retrieved 2 January 2014.
  102. ^ Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 9780071827706. Unlike cocaine and amphetamine, methamphetamine is directly toxic at higher doses to midbrain dopamine neurons
  103. ^ a b c Shoptaw SJ, Kao U, Ling W (2009). Shoptaw SJ, Ali R (eds.). "Treatment for amphetamine psychosis". Cochrane Database Syst. Rev. 2009 (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMC 7004251. 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.
  104. ^ Hofmann FG (1983). A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects (2nd ed.). New York: Oxford University Press. p. 329. ISBN 978-0-19-503057-0.
  105. ^ Berman SM, Kuczenski R, McCracken JT, London ED (February 2009). "Potential adverse effects of amphetamine treatment on brain and behavior: a review". Mol. Psychiatry. 14 (2): 123–142. doi:10.1038/mp.2008.90. PMC 2670101. PMID 18698321.
  106. ^ Spencer MR, Miniño AM, Warner M (December 2022). "Drug Overdose Deaths in the United States, 2001–2021". NCHS Data Brief (457). National Center for Health Statistics (U.S.): 1–8. doi:10.15620/cdc:122556. PMID 36598401. S2CID 254388862.
  107. ^ Parish DC, Goyal H, Dane FC (May 2018). "Mechanism of death: there's more to it than sudden cardiac arrest". Journal of Thoracic Disease. 10 (5): 3081–3087. doi:10.21037/jtd.2018.04.113. PMC 6006107. PMID 29997977.
  108. ^ Noblett D, Hacein-Bey L, Waldau B, Ziegler J, Dahlin B, Chang J (February 2021). "Increased rupture risk in small intracranial aneurysms associated with methamphetamine use". Interventional Neuroradiology. 27 (1): 75–80. doi:10.1177/1591019920959534. PMC 7903554. PMID 32967503.
  109. ^ Paone S, Clarkson L, Sin B, Punnapuzha S (August 2018). "Recognition of Sympathetic Crashing Acute Pulmonary Edema (SCAPE) and use of high-dose nitroglycerin infusion". The American Journal of Emergency Medicine. 36 (8): 1526.e5–1526.e7. doi:10.1016/j.ajem.2018.05.013. PMID 29776826. S2CID 21698404.
  110. ^ Gholami F, Hosseini SH, Ahmadi A, Nabati M (15 October 2019). "A Case report of hemodynamic instability, cardiac arrest, and acute severe dyspnea subsequent to inhalation of crystal methamphetamine". Pharmaceutical and Biomedical Research. doi:10.18502/pbr.v5i2.1585. ISSN 2423-4494. Archived from the original on 26 December 2023. Retrieved 26 December 2023.
  111. ^ De Letter EA, Piette MH, Lambert WE, Cordonnier JA (January 2006). "Amphetamines as potential inducers of fatalities: a review in the district of Ghent from 1976-2004". Medicine, Science, and the Law. 46 (1): 37–65. doi:10.1258/rsmmsl.46.1.37. PMID 16454462.
  112. ^ a b c Richards JR, Albertson TE, Derlet RW, Lange RA, Olson KR, Horowitz BZ (May 2015). "Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review". Drug Alcohol Depend. 150: 1–13. doi:10.1016/j.drugalcdep.2015.01.040. PMID 25724076.
  113. ^ Richards JR, Derlet RW, Duncan DR (September 1997). "Methamphetamine toxicity: treatment with a benzodiazepine versus a butyrophenone". Eur. J. Emerg. Med. 4 (3): 130–135. doi:10.1097/00063110-199709000-00003. PMID 9426992.
  114. ^ Richards JR, Derlet RW, Albertson TE. "Methamphetamine Toxicity: Treatment & Management". Medscape. WebMD. Archived from the original on 9 April 2016. Retrieved 20 April 2016.
  115. ^ a b "Methamphetamine: Enzymes". DrugBank. University of Alberta. 8 February 2013. Archived from the original on 28 December 2015. Retrieved 2 January 2014.
  116. ^ a b c Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
  117. ^ a b c "Methamphetamine: Targets". DrugBank. University of Alberta. 8 February 2013. Archived from the original on 28 December 2015. Retrieved 4 January 2014.
  118. ^ Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, et al. (July 2001). "Trace amines: identification of a family of mammalian G protein-coupled receptors". Proc. Natl. Acad. Sci. U.S.A. 98 (16): 8966–8971. Bibcode:2001PNAS...98.8966B. doi:10.1073/pnas.151105198. PMC 55357. PMID 11459929.
  119. ^ Xie Z, Miller GM (July 2009). "A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain". J. Pharmacol. Exp. Ther. 330 (1): 316–325. doi:10.1124/jpet.109.153775. PMC 2700171. PMID 19364908.
  120. ^ Maguire JJ, Davenport AP (2 December 2014). "TA1 receptor". IUPHAR database. International Union of Basic and Clinical Pharmacology. Archived from the original on 29 June 2015. Retrieved 8 December 2014.
  121. ^ Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014). "Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons". Neuron. 83 (2): 404–416. doi:10.1016/j.neuron.2014.05.043. PMC 4159050. PMID 25033183. AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012).
  122. ^ Vaughan RA, Foster JD (September 2013). "Mechanisms of dopamine transporter regulation in normal and disease states". Trends Pharmacol. Sci. 34 (9): 489–496. doi:10.1016/j.tips.2013.07.005. PMC 3831354. PMID 23968642. AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].
  123. ^ Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (July 2011). "Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons". Front. Syst. Neurosci. 5: 56. doi:10.3389/fnsys.2011.00056. PMC 3131148. PMID 21772817. 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.
  124. ^ mct (28 January 2012). "TAAR1". GenAtlas. University of Paris. Archived from the original on 29 May 2014. Retrieved 29 May 2014.
     • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)
  125. ^ Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, et al. (May 2011). "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc. Natl. Acad. Sci. U.S.A. 108 (20): 8485–8490. Bibcode:2011PNAS..108.8485R. doi:10.1073/pnas.1103029108. PMC 3101002. PMID 21525407.
  126. ^ a b "Methamphetamine: Transporters". DrugBank. University of Alberta. 8 February 2013. Archived from the original on 28 December 2015. Retrieved 4 January 2014.
  127. ^ Eiden LE, Weihe E (January 2011). "VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse". Ann. N. Y. Acad. Sci. 1216 (1): 86–98. Bibcode:2011NYASA1216...86E. doi:10.1111/j.1749-6632.2010.05906.x. PMC 4183197. PMID 21272013.
  128. ^ Inazu M, Takeda H, Matsumiya T (August 2003). "[The role of glial monoamine transporters in the central nervous system]". Nihon Shinkei Seishin Yakurigaku Zasshi (in Japanese). 23 (4): 171–178. PMID 13677912.
  129. ^ Melega WP, Cho AK, Schmitz D, Kuczenski R, Segal DS (February 1999). "l-methamphetamine pharmacokinetics and pharmacodynamics for assessment of in vivo deprenyl-derived l-methamphetamine". J. Pharmacol. Exp. Ther. 288 (2): 752–758. PMID 9918585.
  130. ^ a b Kuczenski R, Segal DS, Cho AK, Melega W (February 1995). "Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine". J. Neurosci. 15 (2): 1308–1317. doi:10.1523/jneurosci.15-02-01308.1995. PMC 6577819. PMID 7869099.
  131. ^ a b Mendelson J, Uemura N, Harris D, Nath RP, Fernandez E, Jacob P, et al. (October 2006). "Human pharmacology of the methamphetamine stereoisomers". Clin. Pharmacol. Ther. 80 (4): 403–420. doi:10.1016/j.clpt.2006.06.013. PMID 17015058. S2CID 19072636.
  132. ^ a b c d e f g h i j k "Methamphetamine: Pharmacology". DrugBank. University of Alberta. 2 October 2017. Archived from the original on 6 October 2017. Retrieved 5 October 2017. Methamphetamine is rapidly absorbed from the gastrointestinal tract with peak methamphetamine concentrations occurring in 3.13 to 6.3 hours post ingestion. Methamphetamine is also well absorbed following inhalation and following intranasal administration. It is distributed to most parts of the body. Because methamphetamine has a high lipophilicity it is distributed across the blood brain barrier and crosses the placenta. ...
    The primary site of metabolism is in the liver by aromatic hydroxylation, N-dealkylation and deamination. At least seven metabolites have been identified in the urine, with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine. Other minor metabolites include 4-hydroxyamphetamine, norephedrine, and 4-hydroxynorephedrine.
  133. ^ Xu J, Zhang Z, Liu R, Sun Y, Liu H, Nie Z, et al. (May 2019). "Function of complement factor H and imaging of small molecules by MALDI-MSI in a methamphetamine behavioral sensitization model". Behavioural Brain Research. 364: 233–244. doi:10.1016/j.bbr.2019.02.002. PMID 30731099. S2CID 72333584. Methamphetamine (METH) is a potent amphetamine-type stimulant that has high abuse potential and can be smoked, snorted, injected, or taken orally. The drug is high in lipid solubility and can cross the blood-brain barrier more readily than amphetamine due to the addition of an extra methyl group.
  134. ^ a b Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection". J. Pharm. Biomed. Anal. 30 (2): 247–255. doi:10.1016/S0731-7085(02)00330-8. PMID 12191709.
  135. ^ Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.). Foye's principles of medicinal chemistry (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN 978-1-60913-345-0. Archived from the original on 13 January 2023. Retrieved 5 October 2017. 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.
  136. ^ Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction" (PDF). J. Biol. Chem. 249 (2): 454–458. doi:10.1016/S0021-9258(19)43051-2. PMID 4809526. Archived (PDF) from the original on 7 October 2018. Retrieved 6 November 2014. 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.
  137. ^ Sjoerdsma A, von Studnitz W (April 1963). "Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate". Br. J. Pharmacol. Chemother. 20 (2): 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x. PMC 1703637. PMID 13977820. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
  138. ^ "butyrate-CoA ligase: Substrate/Product". BRENDA. Technische Universität Braunschweig. Archived from the original on 22 June 2017. Retrieved 5 October 2017.
  139. ^ "glycine N-acyltransferase: Substrate/Product". BRENDA. Technische Universität Braunschweig. Archived from the original on 23 June 2017. Retrieved 5 October 2017.
  140. ^ "p-Hydroxyamphetamine: Compound Summary". PubChem Compound. National Center for Biotechnology Information. Archived from the original on 7 June 2013. Retrieved 4 September 2017.
  141. ^ "p-Hydroxynorephedrine: Compound Summary". PubChem Compound. National Center for Biotechnology Information. Archived from the original on 15 October 2013. Retrieved 4 September 2017.
  142. ^ "Phenylpropanolamine: Compound Summary". PubChem Compound. National Center for Biotechnology Information. Archived from the original on 29 September 2013. Retrieved 4 September 2017.
  143. ^ "Amphetamine". Pubchem Compound. National Center for Biotechnology Information. Archived from the original on 13 October 2013. Retrieved 12 October 2013.
  144. ^ Haiser HJ, Turnbaugh PJ (March 2013). "Developing a metagenomic view of xenobiotic metabolism". Pharmacol. Res. 69 (1): 21–31. doi:10.1016/j.phrs.2012.07.009. PMC 3526672. PMID 22902524.
    Haiser HJ, Turnbaugh PJ (March 2013). "Table 2: Xenobiotics metabolized by the human gut microbiota". Pharmacological Research. 69 (1): 21–31. doi:10.1016/j.phrs.2012.07.009. PMC 3526672. PMID 22902524. Archived from the original on 31 October 2021.
  145. ^ Caldwell J, Hawksworth GM (May 1973). "The demethylation of methamphetamine by intestinal microflora". The Journal of Pharmacy and Pharmacology. 25 (5): 422–424. doi:10.1111/j.2042-7158.1973.tb10043.x. PMID 4146404. S2CID 34050001.
  146. ^ 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.
  147. ^ Kraemer T, Maurer HH (August 1998). "Determination of amphetamine, methamphetamine and amphetamine-derived designer drugs or medicaments in blood and urine". J. Chromatogr. B. 713 (1): 163–187. doi:10.1016/S0378-4347(97)00515-X. PMID 9700558.
  148. ^ Kraemer T, Paul LD (August 2007). "Bioanalytical procedures for determination of drugs of abuse in blood". Anal. Bioanal. Chem. 388 (7): 1415–1435. doi:10.1007/s00216-007-1271-6. PMID 17468860. S2CID 32917584.
  149. ^ Goldberger BA, Cone EJ (July 1994). "Confirmatory tests for drugs in the workplace by gas chromatography-mass spectrometry". J. Chromatogr. A. 674 (1–2): 73–86. doi:10.1016/0021-9673(94)85218-9. PMID 8075776.
  150. ^ a b Paul BD, Jemionek J, Lesser D, Jacobs A, Searles DA (September 2004). "Enantiomeric separation and quantitation of (+/-)-amphetamine, (+/-)-methamphetamine, (+/-)-MDA, (+/-)-MDMA, and (+/-)-MDEA in urine specimens by GC-EI-MS after derivatization with (R)-(−)- or (S)-(+)-alpha-methoxy-alpha-(trifluoromethy)phenylacetyl chloride (MTPA)". J. Anal. Toxicol. 28 (6): 449–455. doi:10.1093/jat/28.6.449. PMID 15516295.
  151. ^ de la Torre R, Farré M, Navarro M, Pacifici R, Zuccaro P, Pichini S (2004). "Clinical pharmacokinetics of amfetamine and related substances: monitoring in conventional and non-conventional matrices". Clin Pharmacokinet. 43 (3): 157–185. doi:10.2165/00003088-200443030-00002. PMID 14871155. S2CID 44731289.
  152. ^ Baselt RC (2020). Disposition of toxic drugs and chemicals in man. Seal Beach, Ca.: Biomedical Publications. pp. 1277–1280. ISBN 978-0-578-57749-4.
  153. ^ Venkatratnam A, Lents NH (July 2011). "Zinc reduces the detection of cocaine, methamphetamine, and THC by ELISA urine testing". J. Anal. Toxicol. 35 (6): 333–340. doi:10.1093/anatox/35.6.333. PMID 21740689.
  154. ^ Hakey P, Ouellette W, Zubieta J, Korter T (April 2008). "Redetermination of (+)-methamphetamine hydro-chloride at 90 K". Acta Crystallographica Section E. 64 (Pt 5): o940. Bibcode:2008AcCrE..64O.940H. doi:10.1107/S1600536808011550. PMC 2961146. PMID 21202421.
  155. ^ Nakayama MT. "Chemical Interaction of Bleach and Methamphetamine: A Study of Degradation and Transformation Effects". gradworks. UNIVERSITY OF CALIFORNIA, DAVIS. Archived from the original on 19 October 2014. Retrieved 17 October 2014.
  156. ^ 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. Bibcode:2011Chmsp..85.1002P. doi:10.1016/j.chemosphere.2011.06.102. PMID 21777940.
  157. ^ 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. Bibcode:2013WatRe..47.5708B. doi:10.1016/j.watres.2013.06.057. PMID 23886544.
  158. ^ Crossley FS, Moore ML (November 1944). "Studies on the Leuckart reaction". The Journal of Organic Chemistry. 9 (6): 529–536. doi:10.1021/jo01188a006.
  159. ^ a b c d e Kunalan V, Nic Daéid N, Kerr WJ, Buchanan HA, McPherson AR (September 2009). "Characterization of route specific impurities found in methamphetamine synthesized by the Leuckart and reductive amination methods". Anal. Chem. 81 (17): 7342–7348. doi:10.1021/ac9005588. PMC 3662403. PMID 19637924.
  160. ^ "Overdose Death Rates". National Institute on Drug Abuse (NIDA). Archived from the original on 13 December 2017.
  161. ^ "US overdose deaths from fentanyl and synthetic opioids doubled in 2016". The Guardian. 3 September 2017. Archived from the original on 17 August 2018. Retrieved 17 August 2018.
  162. ^ Rassool GH (2009). Alcohol and Drug Misuse: A Handbook for Students and Health Professionals. London: Routledge. p. 113. ISBN 978-0-203-87117-1.
  163. ^ a b "Historical overview of methamphetamine". Vermont Department of Health. Government of Vermont. Archived from the original on 20 June 2012. Retrieved 29 January 2012.
  164. ^ Grobler SR, Chikte U, Westraat J (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.
  165. ^ "Historical overview of methamphetamine". Vermont Department of Health. Archived from the original on 20 June 2012. Retrieved 15 January 2012.
  166. ^ Pervitin (in German), Berlin: CHEMIE.DE Information Service GmbH, archived from the original on 18 December 2019, retrieved 16 September 2015
  167. ^ Freye E (2009). Pharmacology and Abuse of Cocaine, Amphetamines, Ecstasy and Related Designer Drugs. University Düsseldorf, Germany: Springer. p. 110. ISBN 978-90-481-2447-3.
  168. ^ Ulrich A (6 May 2005). "The Nazi Death Machine: Hitler's Drugged Soldiers". Spiegel Online. Der Spiegel, 6 May 2005. Archived from the original on 19 December 2017. Retrieved 12 August 2014.
  169. ^ Defalque RJ, Wright AJ (April 2011). "Methamphetamine for Hitler's Germany: 1937 to 1945". Bull. Anesth. Hist. 29 (2): 21–24, 32. doi:10.1016/s1522-8649(11)50016-2. PMID 22849208.
  170. ^ a b Kamieński Ł (2016). Shooting Up: A Short History of Drugs and War. Oxford University Press. pp. 111–13. ISBN 978-0-19-026347-8. Archived from the original on 23 March 2017. Retrieved 23 October 2016.
  171. ^ a b Rasmussen N (March 2008). On Speed: The Many Lives of Amphetamine (1 ed.). New York University Press. p. 148. ISBN 978-0-8147-7601-8.
  172. ^ "Controlled Substances Act". United States Food and Drug Administration. 11 June 2009. Archived from the original on 5 April 2017. Retrieved 4 November 2013.
  173. ^ "Desoxyn". Lundbeck: Desoxyn. Archived from the original on 30 November 2012. Retrieved 15 December 2012.
  174. ^ "Recordati: Desoxyn". Recordati SP. Archived from the original on 7 July 2013. Retrieved 15 May 2013.
  175. ^ "Transnational Organized Crime in Southeast Asia: Evolution, Growth and Challenges" (PDF). June 2019. Archived from the original on 22 January 2021. Retrieved 30 July 2020.
  176. ^ "The Man Accused of Running the Biggest Drug Trafficking Syndicate in Asia's History has Been Revealed: Here's What Needs To Happen Next". CNN. 24 October 2019. Archived from the original on 22 October 2021. Retrieved 30 July 2020.
  177. ^ Smith N (14 October 2019). "Drugs investigators close in on Asian 'El Chapo' at centre of vast meth ring". The Telegraph. Archived from the original on 10 January 2022.
  178. ^ "Inside the hunt for the man known as 'Asia's El Chapo'". New York Post. 14 October 2019. Archived from the original on 19 January 2021. Retrieved 30 July 2020.
  179. ^ a b "Notorious drug kingpin executed for trafficking". South China Morning Post. 16 September 2009. Archived from the original on 3 June 2022. Retrieved 3 June 2022.
  180. ^ 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. Archived (PDF) from the original on 16 October 2013. Retrieved 11 November 2013.
  181. ^ a b "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.
  182. ^ Rau TF, Kothiwal AS, Rova AR, Brooks DM, Poulsen DJ (August 2012). "Treatment with low-dose methamphetamine improves behavioral and cognitive function after severe traumatic brain injury". The Journal of Trauma and Acute Care Surgery. 73 (2 Suppl 1): S165–S172. doi:10.1097/TA.0b013e318260896a. PMID 22847088.
  183. ^ O'Phelan K, McArthur DL, Chang CW, Green D, Hovda DA (September 2008). "The impact of substance abuse on mortality in patients with severe traumatic brain injury". The Journal of Trauma. 65 (3): 674–677. doi:10.1097/TA.0b013e31817db0a5. PMID 18784583.
  184. ^ Cass WA, Smith MP, Peters LE (August 2006). "Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine". Annals of the New York Academy of Sciences. 1074 (1): 261–271. Bibcode:2006NYASA1074..261C. doi:10.1196/annals.1369.023. PMID 17105922. S2CID 8537458.
  185. ^ Huang YN, Yang LY, Wang JY, Lai CC, Chiu CT, Wang JY (January 2017). "L-Ascorbate Protects Against Methamphetamine-Induced Neurotoxicity of Cortical Cells via Inhibiting Oxidative Stress, Autophagy, and Apoptosis". Molecular Neurobiology. 54 (1): 125–136. doi:10.1007/s12035-015-9561-z. PMID 26732595.
  186. ^ Moshiri M, Hosseiniyan SM, Moallem SA, Hadizadeh F, Jafarian AH, Ghadiri A, et al. (April 2018). "The effects of vitamin B12 on the brain damages caused by methamphetamine in mice". Iranian Journal of Basic Medical Sciences. 21 (4): 434–438. doi:10.22038/IJBMS.2018.23362.5897. PMC 5960763. PMID 29796230.
  187. ^ Anazodo G (May 2024). "Protective effects of vitamin C and E on amygdala of methamphetamine-induced brain disorder on adult male Wistar rats" (PDF). World Journal of Pharmaceutical Research. 13 (9): 2121–2170. Archived (PDF) from the original on 22 September 2024. Retrieved 19 September 2024.

Further reading

Wikimedia Commons has media related to Dextromethamphetamine.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Methamphetamine&oldid=1254939132#Medical"