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Wikipedia

Methamphetamine

March 18, 2023

"Meth" redirects here. For other uses, see Meth (disambiguation). "Hiropon" redirects here. For the sculpture, see Hiropon (sculpture).

Methamphetamine[note 1] (contracted from N-methylamphetamine) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity.[17] 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. It is rarely prescribed over concerns involving human neurotoxicity and 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. Dextroamphetamine is a stronger CNS stimulant than levomethamphetamine.

Methamphetamine
Clinical data
Pronunciation/ˌmɛθæmˈfɛtəmiːn/
(METH-am-FET-ə-meen), /ˌmɛθəmˈfɛtəmiːn/
(METH-əm-FET-ə-meen), /ˌmɛθəmˈfɛtəmən/
(METH-əm-FET-ə-mən)[1]
Trade namesDesoxyn, Methedrine
Other namesN-methylamphetamine, N,α-dimethylphenethylamine, desoxyephedrine
AHFS/Drugs.comMonograph
License data
  • US FDA: Methamphetamine
Dependence
liability		Physical: None; Psychological: High
Addiction
liability		High
Routes of
administration		Medical: oral (ingestion)
Recreational: oral, intravenous, intramuscular, subcutaneous, vapour inhalation, insufflation, rectal, vaginal
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: 67%[2][3][4][5]
Intranasal: 79%[2][3]
Inhalation: 67–90%[2][3][4]
Intravenous: 100%[2][5]
Protein bindingVaries widely[6]
MetabolismCYP2D6[7][8] and FMO3[9][10]
Onset of actionOral: 3 hours (peak)[2]
Intranasal: <15 minutes[2]
Inhalation: <18 minutes[2][3]
Intravenous: <15 minutes[2]
Elimination half-life9–12 hours (range 5–30 hours) (irrespective of route)[3][2]
Duration of action8–12 hours[4]
ExcretionPrimarily kidney
Identifiers
  • (RS)-N-methyl-1-phenylpropan-2-amine
CAS Number
  • 537-46-2 Y
  • (dl)-Methamphetamine hydrochloride: 300-42-5 Y
PubChem CID
  • 1206
IUPHAR/BPS
  • 4803
DrugBank
  • DB01577 Y
ChemSpider
  • 1169 Y
UNII
  • 44RAL3456C
  • (dl)-Methamphetamine hydrochloride: 24GNZ56D62 Y
KEGG
  • D08187 Y
ChEBI
  • CHEBI:6809 Y
ChEMBL
  • ChEMBL1201201 Y
PDB ligand
  • B40 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID8037128
ECHA InfoCard100.007.882
Chemical and physical data
FormulaC10H15N
Molar mass149.237 g·mol−1
3D model (JSmol)
  • Interactive image
ChiralityRacemic mixture
Melting point170 °C (338 °F) [11]
Boiling point212 °C (414 °F) at 760 mmHg[11]
  • 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 Y
  • Key:MYWUZJCMWCOHBA-UHFFFAOYSA-N Y
  (verify)

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.[21] 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). Withdrawal from methamphetamine after heavy use may lead to a post-acute-withdrawal syndrome, which can persist for months beyond the typical withdrawal period. Methamphetamine is neurotoxic to human midbrain dopaminergic neurons at high doses. Methamphetamine has been shown to have a higher affinity and, as a result, higher toxicity toward serotonergic neurons than amphetamine.[22][23] 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.[23]

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, under the trade name Desoxyn, has been approved by the FDA for treating ADHD and obesity in both adults and children;[24][25] however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use.[24] Methamphetamine is sometimes prescribed off label for narcolepsy and idiopathic hypersomnia.[26][27] In the United States, methamphetamine's levorotary form is available in some over-the-counter (OTC) nasal decongestant products.[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.[24] Methamphetamine hydrochloride dispensed in the United States is required to include a boxed warning regarding its potential for recreational misuse and addiction liability.[24]

Desoxyn and Desoxyn Gradumet are both pharmaceutical forms of the drug. The latter is no longer produced and is a gradual-release form of the drug, flattening the curve of the effect of the drug while extending it. [28]

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.[29]

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.[29] Participants in this subculture, which consists almost entirely of homosexual male methamphetamine users, will typically meet up through internet dating sites and have sex.[29] 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.[29] The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia (excessive daytime sleepiness).[29] The party and play subculture is prevalent in major US cities such as San Francisco and New York City.[29][30]

 
Desoxyn tablets – pharmaceutical methamphetamine hydrochloride
 
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.[24] 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.[24] 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.[24] Owing to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.[24]

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.[31]

Physical

The physical effects of methamphetamine can include loss of appetite, hyperactivity, dilated pupils, flushed skin, excessive sweating, increased movement, dry mouth and teeth grinding (leading to "meth mouth"), headache, irregular heartbeat (usually as accelerated heartbeat or slowed heartbeat), rapid breathing, high blood pressure, low blood pressure, high body temperature, diarrhea, constipation, blurred vision, dizziness, twitching, numbness, tremors, dry skin, acne, and pale appearance.[24][32] Long-term meth users may have sores on their skin;[33][34][35] these may be caused by scratching due to itchiness[34] or the belief that insects are crawling under their skin,[33] and the damage is compounded by poor diet and hygiene.[35] Numerous deaths related to methamphetamine overdoses have been reported.[36][37]

Meth mouth

Main article: Meth mouth
 
A suspected case of meth mouth

Methamphetamine users and addicts may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as meth mouth.[38] The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it.[38] 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)".[38][39] 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.[25]

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.[40] 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.[40] 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.[24][41] Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.[24][41]

Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle.[42] The level of needle sharing among methamphetamine users is similar to that among other drug injection users.[42]

Fatal

Doses of 200 mg or more of methamphetamine are considered fatal.[43]

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.[24][32][44] Peculiar to methamphetamine and related stimulants is "punding", persistent non-goal-directed repetitive activity.[45] Methamphetamine use also has a high association with anxiety, depression, amphetamine psychosis, suicide, and violent behaviors.[46][47]

Neurotoxic and neuroimmunological

 
This diagram depicts the neuroimmune mechanisms that mediate methamphetamine-induced neurodegeneration in the human brain.[48] 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.[48][49][50]

Methamphetamine is directly neurotoxic to dopaminergic neurons in both lab animals and humans.[22][23] Excitotoxicity, oxidative stress, metabolic compromise, UPS dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression and other processes contributed to this neurotoxicity.[51][52][53] In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of Parkinson's disease.[54] 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.[23] It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.[55] Withdrawal of methamphetamine in dependent persons may lead to post-acute withdrawal which persists months beyond the typical withdrawal period.[53]

Magnetic resonance imaging studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse neuroplastic changes in brain structure and function.[23] 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.[23] 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.[23]

Methamphetamine has been shown to activate TAAR1 in human astrocytes and generate cAMP as a result.[54] 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.[54]

Methamphetamine binds to and activates both sigma receptor subtypes, σ1 and σ2, with micromolar affinity.[50][56] 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.[50][56]

Addictive

Addiction and dependence glossary[57][58][59][60]
  • 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 that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia)
  • 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
 
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,[61][62] 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.[61][63][64] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[61][65][66] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[67] 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.[65][66] 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.[65][66]

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.[68][69] 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).[69] 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.[58][69][71] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[58][71] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[69][71][72][73][74]

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).[58][69][75] 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).[69] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[69][72][76] 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.[69][72] 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][72][77] 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.[72][76][77]

Epigenetic factors

Methamphetamine addiction is persistent for many individuals, with 61% of individuals treated for addiction relapsing within one year.[78] 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.[79]

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.[80]

A review in 2015[81] 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).[81] c-fos is well known to be important in addiction.[82] The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.[81]

In methamphetamine addicted rats, epigenetic regulation through reduced acetylation of histones, in brain striatal neurons, caused reduced transcription of glutamate receptors.[83] Glutamate receptors play an important role in regulating the reinforcing effects of misused illicit drugs.[84]

Administration of methamphetamine to rodents causes DNA damage in their brain, particularly in the nucleus accumbens region.[85][86] 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.[87] 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).[88] 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.[88]

As of December 2019, there is no effective pharmacotherapy for methamphetamine addiction.[89][90][91] A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for amphetamine and methamphetamine addiction;[90] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.[90] 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.[90]

Dependence and withdrawal

Tolerance is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly.[92][93] In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.[94] Depression from methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.[95]

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".[94] 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.[94] 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.[94]

Methamphetamine that is present in a mother's bloodstream can pass through the placenta to a fetus and be secreted into breast milk.[95] Infants born to methamphetamine-abusing mothers may experience a neonatal withdrawal syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and hypertonia.[95] This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.[95]

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 MSNs 		↑ ↑ ↑ ↑ ↑ ↑ [72]
Behavioral plasticity
Escalation of intake Yes Yes Yes [72]
Psychostimulant
cross-sensitization 		Yes Not applicable Yes Yes Attenuated Attenuated [72]
Psychostimulant
self-administration 		↑ ↑ ↓ ↓ ↓ [72]
Psychostimulant
conditioned place preference 		↑ ↑ ↓ ↑ ↓ ↑ [72]
Reinstatement of drug-seeking behavior ↑ ↑ ↓ ↓ [72]
Neurochemical plasticity
CREB phosphorylation
in the nucleus accumbens 		↓ ↓ ↓ ↓ ↓ [72]
Sensitized dopamine response
in the nucleus accumbens 		No Yes No Yes [72]
Altered striatal dopamine signaling ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD2 ↑DRD2 [72]
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 [72]
Changes in striatal opioid peptides ↑dynorphin
No change: enkephalin		 ↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin [72]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens ↓ ↑ ↑ [72]
Dendritic spine density in
the nucleus accumbens 		↓ ↑ ↑ [72]

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.[96]

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.[97]

Overdose

See also: Aimo Koivunen

A methamphetamine overdose may result in a wide range of symptoms.[3][24] 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.[3][32] 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, hyperpyrexia (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.[101][23] Death from methamphetamine poisoning is typically preceded by convulsions and coma.[24]

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).[3][102] 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.[102][103] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[102] Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[104]

Emergency treatment

Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of activated charcoal and sedation.[3] There is not enough evidence on hemodialysis or peritoneal dialysis in cases of methamphetamine intoxication to determine their usefulness.[24] 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.[3] Hypertension presents a risk for intracranial hemorrhage (i.e., bleeding in the brain) and, if severe, is typically treated with intravenous phentolamine or nitroprusside.[3] Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment.[3]

Antipsychotics such as haloperidol are useful in treating agitation and psychosis from methamphetamine overdose.[105][106] Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity.[107] The mixed alpha- and beta-blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.[105] The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.[105]

Interactions

Methamphetamine is metabolized by the liver enzyme CYP2D6, so CYP2D6 inhibitors will prolong the elimination half-life of methamphetamine.[108] Methamphetamine also interacts with monoamine oxidase inhibitors (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.[24] Methamphetamine may decrease the effects of sedatives and depressants and increase the effects of antidepressants and other stimulants as well.[24] Methamphetamine may counteract the effects of antihypertensives and antipsychotics owing to its effects on the cardiovascular system and cognition respectively.[24] The pH of gastrointestinal content and urine affects the absorption and excretion of methamphetamine.[24] Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite.[24] Owing to the effect pH has on absorption, proton pump inhibitors, which reduce gastric acid, are known to interact with methamphetamine.[24]

Pharmacology

 
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.[109][110] 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).[109][111] 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.[109][112] 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.[113][114][115] TAAR1 has been shown to reduce the firing rate of neurons through direct activation of G protein-coupled inwardly-rectifying potassium channels.[116][117][118] TAAR1 activation by methamphetamine in astrocytes appears to negatively modulate the membrane expression and function of EAAT2, a type of glutamate transporter.[54]

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.[119] 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.[120] Other transporters that methamphetamine is known to inhibit are SLC22A3 and SLC22A5.[119] SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.[110][121]

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).[50][110][56] Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain.[50][56] Dextromethamphetamine is a stronger psychostimulant, but levomethamphetamine has stronger peripheral effects, a longer half-life, and longer perceived effects among addicts.[122][123][124] At high doses, both enantiomers of methamphetamine can induce similar stereotypy and methamphetamine psychosis,[123] but levomethamphetamine has shorter psychodynamic effects.[124]

Pharmacokinetics

The bioavailability of methamphetamine is 67% orally, 79% intranasally, 67 to 90% via inhalation (smoking), and 100% intravenously.[2][3][4] 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.[125] Methamphetamine is also well absorbed following inhalation and following intranasal administration.[3] Because of the high lipophilicity of methamphetamine, it can readily move through the blood–brain barrier faster than other stimulants, where it is more resistant to degradation by monoamine oxidase.[3][125] The amphetamine metabolite peaks at 10–24 hours.[3] Methamphetamine is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH.[24][125] When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine.[125] Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine.[125] The elimination half-life of methamphetamine varies with a range of 5–30 hours, however it is on average 9 to 12 hours in most studies.[3][2] The elimination half-life of methamphetamine does not vary by route of administration, but is subject to substantial interindividual variability.[2]

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;[125] other minor metabolites include: 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone, the metabolites of amphetamine.[8][125][126] Among these metabolites, the active sympathomimetics are amphetamine, 4‑hydroxyamphetamine,[132] 4‑hydroxynorephedrine,[133] 4-hydroxymethamphetamine,[125] and norephedrine.[134] Methamphetamine is a CYP2D6 inhibitor.[108]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[8][125][135] The known metabolic pathways include:

Metabolic pathways of methamphetamine in humans[sources 2]
 
The primary metabolites of methamphetamine are amphetamine and 4-hydroxymethamphetamine.[125] 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.[136][137]

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.[138][139][140][141] 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.[142] 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.[142][143][144] Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.[145]

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.[11] It is soluble in diethyl ether and ethanol as well as miscible with chloroform.[11]

In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste.[11] 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.[11] The hydrochloride salt is also freely soluble in ethanol and water.[11] Its crystal structure 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°.[146]

Degradation

A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration.[147] A year-long study (also from 2011) showed that methamphetamine in soils is a persistent pollutant.[148] In a 2013 study of bioreactors in wastewater, methamphetamine was found to be largely degraded within 30 days under exposure to light.[149]

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[150] or reductive amination methods.[151] 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.[151] In this reaction, an iminium cation is formed as an intermediate which is reduced by the second equivalent of N-methylformamide.[151] The intermediate formyl amide is then hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product.[151] Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.[151]

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

History, society, and culture

Main article: History and culture of substituted amphetamines
 
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).[152][153]

Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine.[154][155] Shortly after, methamphetamine was synthesized from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi.[156] Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.[157]

Since 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.[158][159] It was used by all branches of the combined armed forces of the Third Reich, for its stimulant effects and to induce extended wakefulness.[160][161] 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.[162] 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.[162]

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.[163] Because of the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s.[163] Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.[155] For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act.[164] Currently, methamphetamine is sold under the trade name Desoxyn, trademarked by the Danish pharmaceutical company Lundbeck.[165] As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.[166]

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.[167]

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.[168] 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.[169] 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.[170] 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.[171] It was estimated over 18 tonnes of methamphetamine were produced under his watch.[171]

Legal status

Main article: Legal status of methamphetamine

The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions.[172][173] Methamphetamine has been placed in schedule II of the United Nations Convention on Psychotropic Substances treaty.[173]

Research

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.[174]

See also

Explanatory notes

  1. ^ Synonyms and alternate spellings include: N-methylamphetamine, desoxyephedrine, Syndrox, Methedrine, and Desoxyn.[12][13][14] Common slang terms for methamphetamine include: speed, meth, crystal, crystal meth, glass, shards, ice, tic, and Tina,[15] and, in New Zealand, "P".[16]
  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.[12][18]
  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.[19][20]
  4. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[70]
  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.

Image legend

  1. ^
      Ion channel
      G proteins & linked receptors
      (Text color) Transcription factors

Reference notes

  1. ^ [3][24][32][44][98][99][100]
  2. ^ a b [7][8][9][10][125][126][127][128][129][130][131]

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Further reading

  • Szalavitz M. "Why the Myth of the Meth-Damaged Brain May Hinder Recovery". Time.com. Time USA, LLC.
  • 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. ISSN 0893-133X. PMC 3260986. PMID 22089317.
    • Szalavitz M (21 November 2011). "Why the Myth of the Meth-Damaged Brain May Hinder Recovery". Time.

External links

 
Wikimedia Commons has media related to Dextromethamphetamine.
  • Methamphetamine Toxnet entry
  • Methamphetamine Poison Information Monograph
  • Drug Trafficking: Aryan Brotherhood Methamphetamine Operation Dismantled, FBI
  • Neurologic manifestations of chronic methamphetamine abuse

March 18, 2023
methamphetamine, meth, redirects, here, other, uses, meth, disambiguation, hiropon, redirects, here, sculpture, hiropon, sculpture, note, contracted, from, methylamphetamine, potent, central, nervous, system, stimulant, that, mainly, used, recreational, drug, . Meth redirects here For other uses see Meth disambiguation Hiropon redirects here For the sculpture see Hiropon sculpture Methamphetamine note 1 contracted from N methylamphetamine is a potent central nervous system CNS stimulant that is mainly used as a recreational drug and less commonly as a second line treatment for attention deficit hyperactivity disorder and obesity 17 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 It is rarely prescribed over concerns involving human neurotoxicity and 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 Dextroamphetamine is a stronger CNS stimulant than levomethamphetamine MethamphetamineClinical dataPronunciation ˌ m ɛ 8 ae m ˈ f ɛ t em iː n METH am FET e meen ˌ m ɛ 8 e m ˈ f ɛ t em iː n METH em FET e meen ˌ m ɛ 8 e m ˈ f ɛ t em e n METH em FET e men 1 Trade namesDesoxyn MethedrineOther namesN methylamphetamine N a dimethylphenethylamine desoxyephedrineAHFS Drugs comMonographLicense dataUS FDA MethamphetamineDependenceliabilityPhysical None Psychological HighAddictionliabilityHighRoutes ofadministrationMedical oral ingestion Recreational oral intravenous intramuscular subcutaneous vapour inhalation insufflation rectal vaginalATC codeN06BA03 WHO Legal statusLegal statusAU S8 Controlled drug BR Class A3 Psychoactive drugs CA Schedule I DE Anlage II Authorized trade only not prescriptible NZ Class A UK Class A US Schedule II UN Psychotropic Schedule IIPharmacokinetic dataBioavailabilityOral 67 2 3 4 5 Intranasal 79 2 3 Inhalation 67 90 2 3 4 Intravenous 100 2 5 Protein bindingVaries widely 6 MetabolismCYP2D6 7 8 and FMO3 9 10 Onset of actionOral 3 hours peak 2 Intranasal lt 15 minutes 2 Inhalation lt 18 minutes 2 3 Intravenous lt 15 minutes 2 Elimination half life9 12 hours range 5 30 hours irrespective of route 3 2 Duration of action8 12 hours 4 ExcretionPrimarily kidneyIdentifiersIUPAC name RS N methyl 1 phenylpropan 2 amineCAS Number537 46 2 Y dl Methamphetamine hydrochloride 300 42 5 YPubChem CID1206IUPHAR BPS4803DrugBankDB01577 YChemSpider1169 YUNII44RAL3456C dl Methamphetamine hydrochloride 24GNZ56D62 YKEGGD08187 YChEBICHEBI 6809 YChEMBLChEMBL1201201 YPDB ligandB40 PDBe RCSB PDB CompTox Dashboard EPA DTXSID8037128ECHA InfoCard100 007 882Chemical and physical dataFormulaC 10H 15NMolar mass149 237 g mol 13D model JSmol Interactive imageChiralityRacemic mixtureMelting point170 C 338 F 11 Boiling point212 C 414 F at 760 mmHg 11 SMILES CNC C Cc1ccccc1InChI InChI 1S C10H15N c1 9 11 2 8 10 6 4 3 5 7 10 h3 7 9 11H 8H2 1 2H3 YKey MYWUZJCMWCOHBA UHFFFAOYSA N Y verify 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 21 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 Withdrawal from methamphetamine after heavy use may lead to a post acute withdrawal syndrome which can persist for months beyond the typical withdrawal period Methamphetamine is neurotoxic to human midbrain dopaminergic neurons at high doses Methamphetamine has been shown to have a higher affinity and as a result higher toxicity toward serotonergic neurons than amphetamine 22 23 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 23 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 Contents 1 Uses 1 1 Medical 1 2 Recreational 2 Contraindications 3 Adverse effects 3 1 Physical 3 1 1 Meth mouth 3 1 2 Sexually transmitted infection 3 2 Fatal 3 3 Psychological 3 4 Neurotoxic and neuroimmunological 3 5 Addictive 3 5 1 Epigenetic factors 3 5 2 Treatment and management 3 5 3 Dependence and withdrawal 3 6 Neonatal 4 Overdose 4 1 Psychosis 4 2 Emergency treatment 5 Interactions 6 Pharmacology 6 1 Pharmacodynamics 6 2 Pharmacokinetics 6 2 1 Detection in biological fluids 7 Chemistry 7 1 Degradation 7 2 Synthesis 8 History society and culture 9 Trafficking 10 Legal status 11 Research 12 See also 13 Explanatory notes 14 Reference notes 15 References 16 Further reading 17 External linksUsesMedical Desoxyn Methamphetamine Hydrochloride 100 tablets In the United States methamphetamine hydrochloride under the trade name Desoxyn has been approved by the FDA for treating ADHD and obesity in both adults and children 24 25 however the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use 24 Methamphetamine is sometimes prescribed off label for narcolepsy and idiopathic hypersomnia 26 27 In the United States methamphetamine s levorotary form is available in some over the counter OTC nasal decongestant products 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 24 Methamphetamine hydrochloride dispensed in the United States is required to include a boxed warning regarding its potential for recreational misuse and addiction liability 24 Desoxyn and Desoxyn Gradumet are both pharmaceutical forms of the drug The latter is no longer produced and is a gradual release form of the drug flattening the curve of the effect of the drug while extending it 28 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 29 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 29 Participants in this subculture which consists almost entirely of homosexual male methamphetamine users will typically meet up through internet dating sites and have sex 29 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 29 The crash following the use of methamphetamine in this manner is very often severe with marked hypersomnia excessive daytime sleepiness 29 The party and play subculture is prevalent in major US cities such as San Francisco and New York City 29 30 Desoxyn tablets pharmaceutical methamphetamine hydrochloride Crystal meth illicit methamphetamine hydrochlorideContraindicationsMethamphetamine 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 24 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 24 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 24 Owing to the potential for stunted growth the FDA advises monitoring the height and weight of growing children and adolescents during treatment 24 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 31 Physical The physical effects of methamphetamine can include loss of appetite hyperactivity dilated pupils flushed skin excessive sweating increased movement dry mouth and teeth grinding leading to meth mouth headache irregular heartbeat usually as accelerated heartbeat or slowed heartbeat rapid breathing high blood pressure low blood pressure high body temperature diarrhea constipation blurred vision dizziness twitching numbness tremors dry skin acne and pale appearance 24 32 Long term meth users may have sores on their skin 33 34 35 these may be caused by scratching due to itchiness 34 or the belief that insects are crawling under their skin 33 and the damage is compounded by poor diet and hygiene 35 Numerous deaths related to methamphetamine overdoses have been reported 36 37 Meth mouth Main article Meth mouth A suspected case of meth mouth Methamphetamine users and addicts may lose their teeth abnormally quickly regardless of the route of administration from a condition informally known as meth mouth 38 The condition is generally most severe in users who inject the drug rather than swallow smoke or inhale it 38 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 38 39 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 25 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 40 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 40 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 24 41 Methamphetamine may also cause sores and abrasions in the mouth via bruxism increasing the risk of sexually transmitted infection 24 41 Besides the sexual transmission of HIV it may also be transmitted between users who share a common needle 42 The level of needle sharing among methamphetamine users is similar to that among other drug injection users 42 Fatal Doses of 200 mg or more of methamphetamine are considered fatal 43 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 24 32 44 Peculiar to methamphetamine and related stimulants is punding persistent non goal directed repetitive activity 45 Methamphetamine use also has a high association with anxiety depression amphetamine psychosis suicide and violent behaviors 46 47 Neurotoxic and neuroimmunological This diagram depicts the neuroimmune mechanisms that mediate methamphetamine induced neurodegeneration in the human brain 48 The NF kB 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 48 49 50 Methamphetamine is directly neurotoxic to dopaminergic neurons in both lab animals and humans 22 23 Excitotoxicity oxidative stress metabolic compromise UPS dysfunction protein nitration endoplasmic reticulum stress p53 expression and other processes contributed to this neurotoxicity 51 52 53 In line with its dopaminergic neurotoxicity methamphetamine use is associated with a higher risk of Parkinson s disease 54 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 23 It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine 55 Withdrawal of methamphetamine in dependent persons may lead to post acute withdrawal which persists months beyond the typical withdrawal period 53 Magnetic resonance imaging studies on human methamphetamine users have also found evidence of neurodegeneration or adverse neuroplastic changes in brain structure and function 23 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 23 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 23 Methamphetamine has been shown to activate TAAR1 in human astrocytes and generate cAMP as a result 54 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 54 Methamphetamine binds to and activates both sigma receptor subtypes s1 and s2 with micromolar affinity 50 56 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 50 56 Addictive Addiction and dependence glossary 57 58 59 60 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 that involves emotional motivational withdrawal symptoms e g dysphoria and anhedonia 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 dosevteSignaling cascade in the nucleus accumbens that results in psychostimulant addictionvte Note colored text contains article links Nuclear pore Nuclear membrane Plasma membrane Cav1 2 NMDAR AMPAR DRD1 DRD5 DRD2 DRD3 DRD4 Gs Gi o AC cAMP cAMP PKA CaM CaMKII DARPP 32 PP1 PP2B CREB DFosB JunD c Fos SIRT1 HDAC1 Color legend 1 This diagram depicts the signaling events in the brain s reward center that are induced by chronic high dose exposure to psychostimulants that increase the concentration of synaptic dopamine like amphetamine methamphetamine and phenethylamine Following presynaptic dopamine and glutamate co release by such psychostimulants 61 62 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 61 63 64 Phosphorylated CREB increases levels of DFosB which in turn represses the c Fos gene with the help of corepressors 61 65 66 c Fos repression acts as a molecular switch that enables the accumulation of DFosB in the neuron 67 A highly stable phosphorylated form of DFosB one that persists in neurons for 1 2 months slowly accumulates following repeated high dose exposure to stimulants through this process 65 66 DFosB 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 65 66 Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain particularly the nucleus accumbens 68 69 The most important transcription factors note 4 that produce these alterations are DFosB cAMP response element binding protein CREB and nuclear factor kappa B NFkB 69 DFosB 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 58 69 71 Once DFosB is sufficiently overexpressed it induces an addictive state that becomes increasingly more severe with further increases in DFosB expression 58 71 It has been implicated in addictions to alcohol cannabinoids cocaine methylphenidate nicotine opioids phencyclidine propofol and substituted amphetamines among others 69 71 72 73 74 DJunD a transcription factor and G9a a histone methyltransferase enzyme both directly oppose the induction of DFosB in the nucleus accumbens i e they oppose increases in its expression 58 69 75 Sufficiently overexpressing DJunD 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 DFosB 69 DFosB also plays an important role in regulating behavioral responses to natural rewards such as palatable food sex and exercise 69 72 76 Since both natural rewards and addictive drugs induce expression of DFosB 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 69 72 DFosB 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 72 77 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 72 76 77 Epigenetic factors Methamphetamine addiction is persistent for many individuals with 61 of individuals treated for addiction relapsing within one year 78 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 79 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 80 A review in 2015 81 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 81 c fos is well known to be important in addiction 82 The ccr2 gene is also important in addiction since mutational inactivation of this gene impairs addiction 81 In methamphetamine addicted rats epigenetic regulation through reduced acetylation of histones in brain striatal neurons caused reduced transcription of glutamate receptors 83 Glutamate receptors play an important role in regulating the reinforcing effects of misused illicit drugs 84 Administration of methamphetamine to rodents causes DNA damage in their brain particularly in the nucleus accumbens region 85 86 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 87 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 88 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 88 As of December 2019 update there is no effective pharmacotherapy for methamphetamine addiction 89 90 91 A systematic review and meta analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for amphetamine and methamphetamine addiction 90 it found only low strength evidence that methylphenidate might reduce amphetamine or methamphetamine self administration 90 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 90 Dependence and withdrawal Tolerance is expected to develop with regular methamphetamine use and when used recreationally this tolerance develops rapidly 92 93 In dependent users withdrawal symptoms are positively correlated with the level of drug tolerance 94 Depression from methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal 95 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 94 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 94 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 94 Methamphetamine that is present in a mother s bloodstream can pass through the placenta to a fetus and be secreted into breast milk 95 Infants born to methamphetamine abusing mothers may experience a neonatal withdrawal syndrome with symptoms involving of abnormal sleep patterns poor feeding tremors and hypertonia 95 This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4 of cases 95 Summary of addiction related plasticity Form of neuroplasticity or behavioral plasticity Type of reinforcer SourcesOpiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise aerobic EnvironmentalenrichmentDFosB expression innucleus accumbens D1 type MSNs 72 Behavioral plasticityEscalation of intake Yes Yes Yes 72 Psychostimulantcross sensitization Yes Not applicable Yes Yes Attenuated Attenuated 72 Psychostimulantself administration 72 Psychostimulantconditioned place preference 72 Reinstatement of drug seeking behavior 72 Neurochemical plasticityCREB phosphorylationin the nucleus accumbens 72 Sensitized dopamine responsein the nucleus accumbens No Yes No Yes 72 Altered striatal dopamine signaling DRD2 DRD3 DRD1 DRD2 DRD3 DRD1 DRD2 DRD3 DRD2 DRD2 72 Altered striatal opioid signaling No change or m opioid receptors m opioid receptors k opioid receptors m opioid receptors m opioid receptors No change No change 72 Changes in striatal opioid peptides dynorphinNo change enkephalin dynorphin enkephalin dynorphin dynorphin 72 Mesocorticolimbic synaptic plasticityNumber of dendrites in the nucleus accumbens 72 Dendritic spine density inthe nucleus accumbens 72 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 96 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 97 OverdoseSee also Aimo Koivunen A methamphetamine overdose may result in a wide range of symptoms 3 24 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 3 32 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 hyperpyrexia 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 101 23 Death from methamphetamine poisoning is typically preceded by convulsions and coma 24 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 3 102 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 102 103 The same review asserts that based upon at least one trial antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis 102 Amphetamine psychosis may also develop occasionally as a treatment emergent side effect 104 Emergency treatment Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of activated charcoal and sedation 3 There is not enough evidence on hemodialysis or peritoneal dialysis in cases of methamphetamine intoxication to determine their usefulness 24 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 3 Hypertension presents a risk for intracranial hemorrhage i e bleeding in the brain and if severe is typically treated with intravenous phentolamine or nitroprusside 3 Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment 3 Antipsychotics such as haloperidol are useful in treating agitation and psychosis from methamphetamine overdose 105 106 Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity 107 The mixed alpha and beta blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine 105 The phenomenon of unopposed alpha stimulation has not been reported with the use of beta blockers for treatment of methamphetamine toxicity 105 InteractionsMethamphetamine is metabolized by the liver enzyme CYP2D6 so CYP2D6 inhibitors will prolong the elimination half life of methamphetamine 108 Methamphetamine also interacts with monoamine oxidase inhibitors MAOIs since both MAOIs and methamphetamine increase plasma catecholamines therefore concurrent use of both is dangerous 24 Methamphetamine may decrease the effects of sedatives and depressants and increase the effects of antidepressants and other stimulants as well 24 Methamphetamine may counteract the effects of antihypertensives and antipsychotics owing to its effects on the cardiovascular system and cognition respectively 24 The pH of gastrointestinal content and urine affects the absorption and excretion of methamphetamine 24 Specifically acidic substances will reduce the absorption of methamphetamine and increase urinary excretion while alkaline substances do the opposite 24 Owing to the effect pH has on absorption proton pump inhibitors which reduce gastric acid are known to interact with methamphetamine 24 Pharmacology 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 109 110 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 109 111 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 109 112 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 113 114 115 TAAR1 has been shown to reduce the firing rate of neurons through direct activation of G protein coupled inwardly rectifying potassium channels 116 117 118 TAAR1 activation by methamphetamine in astrocytes appears to negatively modulate the membrane expression and function of EAAT2 a type of glutamate transporter 54 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 119 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 120 Other transporters that methamphetamine is known to inhibit are SLC22A3 and SLC22A5 119 SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes and SLC22A5 is a high affinity carnitine transporter 110 121 Methamphetamine is also an agonist of the alpha 2 adrenergic receptors and sigma receptors with a greater affinity for s1 than s2 and inhibits monoamine oxidase A MAO A and monoamine oxidase B MAO B 50 110 56 Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain 50 56 Dextromethamphetamine is a stronger psychostimulant but levomethamphetamine has stronger peripheral effects a longer half life and longer perceived effects among addicts 122 123 124 At high doses both enantiomers of methamphetamine can induce similar stereotypy and methamphetamine psychosis 123 but levomethamphetamine has shorter psychodynamic effects 124 Pharmacokinetics The bioavailability of methamphetamine is 67 orally 79 intranasally 67 to 90 via inhalation smoking and 100 intravenously 2 3 4 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 125 Methamphetamine is also well absorbed following inhalation and following intranasal administration 3 Because of the high lipophilicity of methamphetamine it can readily move through the blood brain barrier faster than other stimulants where it is more resistant to degradation by monoamine oxidase 3 125 The amphetamine metabolite peaks at 10 24 hours 3 Methamphetamine is excreted by the kidneys with the rate of excretion into the urine heavily influenced by urinary pH 24 125 When taken orally 30 54 of the dose is excreted in urine as methamphetamine and 10 23 as amphetamine 125 Following IV doses about 45 is excreted as methamphetamine and 7 as amphetamine 125 The elimination half life of methamphetamine varies with a range of 5 30 hours however it is on average 9 to 12 hours in most studies 3 2 The elimination half life of methamphetamine does not vary by route of administration but is subject to substantial interindividual variability 2 CYP2D6 dopamine b 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 125 other minor metabolites include 4 hydroxyamphetamine 4 hydroxynorephedrine 4 hydroxyphenylacetone benzoic acid hippuric acid norephedrine and phenylacetone the metabolites of amphetamine 8 125 126 Among these metabolites the active sympathomimetics are amphetamine 4 hydroxyamphetamine 132 4 hydroxynorephedrine 133 4 hydroxymethamphetamine 125 and norephedrine 134 Methamphetamine is a CYP2D6 inhibitor 108 The main metabolic pathways involve aromatic para hydroxylation aliphatic alpha and beta hydroxylation N oxidation N dealkylation and deamination 8 125 135 The known metabolic pathways include Metabolic pathways of methamphetamine in humans sources 2 Methamphetamine 4 Hydroxymethamphetamine 4 Hydroxyphenylacetone Phenylacetone Benzoic acid Hippuric acid Amphetamine Norephedrine 4 Hydroxyamphetamine 4 Hydroxynorephedrine The primary metabolites of methamphetamine are amphetamine and 4 hydroxymethamphetamine 125 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 136 137 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 138 139 140 141 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 142 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 142 143 144 Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine 145 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 11 It is soluble in diethyl ether and ethanol as well as miscible with chloroform 11 In contrast the methamphetamine hydrochloride salt is odorless with a bitter taste 11 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 11 The hydrochloride salt is also freely soluble in ethanol and water 11 Its crystal structure is monoclinic with P21 space group at 90 K 183 2 C 297 7 F it has lattice parameters a 7 10 A b 7 29 A c 10 81 A and b 97 29 146 Degradation A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration 147 A year long study also from 2011 showed that methamphetamine in soils is a persistent pollutant 148 In a 2013 study of bioreactors in wastewater methamphetamine was found to be largely degraded within 30 days under exposure to light 149 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 150 or reductive amination methods 151 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 151 In this reaction an iminium cation is formed as an intermediate which is reduced by the second equivalent of N methylformamide 151 The intermediate formyl amide is then hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product 151 Alternatively phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine 151 Methamphetamine synthesis Method of methamphetamine synthesis of methamphetamine via reductive amination Methods of methamphetamine synthesis via the Leuckart reactionHistory society and cultureMain article History and culture of substituted amphetamines 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 152 153 Amphetamine discovered before methamphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine 154 155 Shortly after methamphetamine was synthesized from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi 156 Three decades later in 1919 methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine 157 Since 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 158 159 It was used by all branches of the combined armed forces of the Third Reich for its stimulant effects and to induce extended wakefulness 160 161 Pervitin became colloquially known among the German troops as Stuka Tablets Stuka Tabletten and Herman Goring Pills Hermann Goring Pillen as a snide allusion to Goring 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 162 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 Lukasz Kamienski 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 162 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 163 Because of the psychological and stimulant effects of methamphetamine Obetrol became a popular diet pill in America in the 1950s and 1960s 163 Eventually as the addictive properties of the drug became known governments began to strictly regulate the production and distribution of methamphetamine 155 For example during the early 1970s in the United States methamphetamine became a schedule II controlled substance under the Controlled Substances Act 164 Currently methamphetamine is sold under the trade name Desoxyn trademarked by the Danish pharmaceutical company Lundbeck 165 As of January 2013 the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati 166 TraffickingThe 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 167 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 168 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 169 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 170 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 171 It was estimated over 18 tonnes of methamphetamine were produced under his watch 171 Legal statusMain article Legal status of methamphetamine The production distribution sale and possession of methamphetamine is restricted or illegal in many jurisdictions 172 173 Methamphetamine has been placed in schedule II of the United Nations Convention on Psychotropic Substances treaty 173 ResearchIt 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 174 See also18 MC Breaking Bad a TV drama series centered on illicit methamphetamine synthesis Drug checking Faces of Meth a drug prevention project Harm reduction Methamphetamine in Australia Methamphetamine in Bangladesh Methamphetamine in the Philippines Methamphetamine in the United States Montana Meth Project a Montana based organization aiming to reduce meth use among teenagers Recreational drug use Rolling meth lab a transportable laboratory that is used to illegally produce methamphetamine Ya ba Southeast Asian tablets containing a mixture of methamphetamine and caffeineExplanatory notes Synonyms and alternate spellings include N methylamphetamine desoxyephedrine Syndrox Methedrine and Desoxyn 12 13 14 Common slang terms for methamphetamine include speed meth crystal crystal meth glass shards ice tic and Tina 15 and in New Zealand P 16 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 12 18 a b c The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine the INN and USAN of levomethamphetamine 19 20 Transcription factors are proteins that increase or decrease the expression of specific genes 70 In simpler terms this necessary and sufficient relationship means that DFosB overexpression in the nucleus accumbens and addiction related behavioral and neural adaptations always occur together and never occur alone 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 Image legend Ion channel G proteins amp linked receptors Text color Transcription factorsReference notes 3 24 32 44 98 99 100 a b 7 8 9 10 125 126 127 128 129 130 131 References methamphetamine Methamphetamine Lexico Archived from the original on 14 June 2021 Retrieved 22 April 2022 a b c d e f g h i j k l Cruickshank CC Dyer KR July 2009 A review of the clinical pharmacology of methamphetamine Addiction 104 7 1085 99 doi 10 1111 j 1360 0443 2009 02564 x PMID 19426289 S2CID 37079117 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 a b c d Courtney KE Ray 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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 DFosB 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 DFosB target is cFos as DFosB accumulates with repeated drug exposure it represses c Fos and contributes to the molecular switch whereby DFosB 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 Glossary of Terms Mount Sinai School of Medicine Department of Neuroscience Retrieved 9 February 2015 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 a b c Renthal W Nestler EJ September 2009 Chromatin regulation in drug addiction and depression Dialogues in Clinical Neuroscience 11 3 257 268 PMC 2834246 PMID 19877494 Psychostimulants increase cAMP levels in striatum which activates protein kinase A PKA and leads to phosphorylation of its targets This includes the cAMP response element binding protein CREB the phosphorylation of which induces its association with the histone acetyltransferase CREB binding protein CBP to acetylate histones and facilitate gene activation This is known to occur on many genes including fosB and c fos in response to psychostimulant exposure DFosB 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 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 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PMID 23430970 The 35 37 kD DFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half lives As a result of its stability the DFosB protein persists in neurons for at least several weeks after cessation of drug exposure DFosB overexpression in nucleus accumbens induces NFkB In contrast the ability of DFosB 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 Nestler EJ October 2008 Transcriptional mechanisms of addiction Role of DFosB 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 DFosB 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 DFosB after chronic drug 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active and 4 hydroxymethamphetamine Other minor metabolites include 4 hydroxyamphetamine norephedrine and 4 hydroxynorephedrine 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 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 amp 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 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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 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 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 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 Cass WA Smith MP Peters LE 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 71 Bibcode 2006NYASA1074 261C doi 10 1196 annals 1369 023 PMID 17105922 S2CID 8537458 Further readingSzalavitz M Why the Myth of the Meth Damaged Brain May Hinder Recovery Time com Time USA LLC 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 ISSN 0893 133X PMC 3260986 PMID 22089317 Szalavitz M 21 November 2011 Why the Myth of the Meth Damaged Brain May Hinder Recovery Time External links Wikimedia Commons has media related to Dextromethamphetamine Methamphetamine Toxnet entry Methamphetamine Poison Information Monograph Drug Trafficking Aryan Brotherhood Methamphetamine Operation Dismantled FBI Neurologic manifestations of chronic methamphetamine abuse Retrieved from https en wikipedia org w index php title Methamphetamine amp oldid 1144150898, wikipedia, wiki, book, books, library,

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