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Methamphetamine

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This article is about thestimulant drug. "Meth" and "crystal meth" redirect here. For other uses, seeMeth (disambiguation).
"Hiropon" redirects here. For the sculpture by Takashi Murakami, seeHiropon (sculpture).
Methamphetamine
An image of the methamphetamine compound
Names
Pronunciation/ˌmɛθæmˈfɛtəmiːn/
Trade namesDesoxyn, Methedrine, others
Other namesN-methylamphetamine,N,α-dimethylphenethylamine, desoxyephedrine
  • (RS)-N-methyl-1-phenylpropan-2-amine
Clinical data
Drug classAmphetamine
Main usesRecreational,ADHD,narcolepsy,obesity[1][2]
Side effectsHigh blood pressure,palpitations,elevate mood, trouble sleeping, tremor, diarrhea,sexual dysfunction[2]
Dependence riskPhysical: None; Psychological: High
Addiction riskHigh
Pregnancy
category
Routes of
use		By mouth
Onset of actionRapid[3]
Duration of action10–20 hours[3]
Urine detection5 days[4]
External links
AHFS/Drugs.comMonograph
Legal
License data
Legal status
Pharmacokinetics
BioavailabilityBy mouth: 70%[5]
IV: 100%[5]
Protein bindingVaries widely[6]
MetabolismCYP2D6[7][8] andFMO3[9][10]
Eliminationhalf-life5–30 hours[11]
ExcretionPrimarilykidney
Chemical and physical data
FormulaC10H15N
Molar mass149.237 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Melting point170 °C (338 °F)[12]
Boiling point212 °C (414 °F) at 760 mmHg[12]
  • CNC(C)Cc1ccccc1
  • InChI=1S/C10H15N/c1-9(11-2)8-10-6-4-3-5-7-10/h3-7,9,11H,8H2,1-2H3 checkY
  • Key:MYWUZJCMWCOHBA-UHFFFAOYSA-N checkY

Methamphetamine[note 1] is acentral nervous system (CNS)stimulant mainly used as arecreational drug and less commonly to treatattention deficit hyperactivity disorder,narcolepsy, andobesity.[15][1] Use for obesity is no longer recommended.[2] When taken by mouth effects begin within 30 minutes and may last for up to 24 hours.[2][1]

Common side effects includehigh blood pressure,palpitations,elevate mood, trouble sleeping, tremor, diarrhea, andsexual dysfunction.[2] Other side effects may includepsychosis,mania,seizures,high body temperature, andtics.[2][16] There is a high riskabuse; though deaths directly from use is rare.[2][1] Use during pregnancy may harm the baby and breastfeeding following using is not recommended.[2][17] It is in theamphetamine family of medication.[2]

Methamphetamine was discovered in 1893 and first manufactured in 1919.[18][1] It is most commonly made in illegal facilities in the United States andFar East.[1] Recreationally it may be swallowed, snorted, injected, or smoked.[1] It is classified as aSchedule II controlled substance.[1] The production, distribution, and possession of methamphetamine is restricted or banned in many countries.[19] In Europe it costs about 17 to 64 Euro per gram for an illegal supply as of 2018.[20] About 27 million people used amphetamines, most methamphetamine, in 2019.[21]

Uses

Medical

Methamphetamine (Desoxyn) 100 tablets.

In the United States, methamphetamine hydrochloride, under the trade nameDesoxyn, has been approved by the FDA for treatingADHD andobesity in both adults and children;[22][23] however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use.[22] Methamphetamine is sometimes prescribedoff label fornarcolepsy andidiopathic hypersomnia.[24][25] In the United States,methamphetamine's levorotary form is available in someover-the-counter (OTC)nasal decongestant products.[26][27]

As methamphetamine is associated with a high potential for misuse, the drug is regulated under theControlled Substances Act and islisted under Schedule II in the United States.[22] Methamphetamine hydrochloride dispensed in the United States is required to include aboxed warning regarding its potential forrecreational misuse andaddiction liability.[22]

For ADHD it may be started at a dose of 5 mg twice per day with a typical dose of 10 mg twice per day.[2]

Recreational

See also:Party and play and theRecreational routes of methamphetamine administration

Methamphetamine is often used recreationally for its effects as a potenteuphoriant and stimulant as well asaphrodisiac qualities.[28]

According to aNational Geographic TV documentary on methamphetamine, an entire subculture known asparty and play is based around sexual activity and methamphetamine use.[28] Participants in this subculture, which consists almost entirely of homosexual male methamphetamine users, will typically meet up throughinternet dating sites and have sex.[28] Due to its strong stimulant and aphrodisiac effects and inhibitory effect onejaculation, with repeated use, these sexual encounters will sometimes occur continuously for several days on end.[28] The crash following the use of methamphetamine in this manner is very often severe, with markedhypersomnia (excessive daytime sleepiness).[28] The party and play subculture is prevalent in major US cities such as San Francisco and New York City.[28][29]

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

Contraindications

Methamphetamine iscontraindicated in individuals with a history ofsubstance use disorder,heart disease, or severeagitation or anxiety, or in individuals currently experiencingarteriosclerosis,glaucoma,hyperthyroidism, or severehypertension.[22] The FDA states that individuals who have experiencedhypersensitivity reactions to other stimulants in the past or are currently takingmonoamine oxidase inhibitors should not take methamphetamine.[22] The FDA also advises individuals withbipolar disorder,depression, elevatedblood pressure, liver or kidney problems,mania,psychosis,Raynaud's phenomenon,seizures,thyroid problems,tics, orTourette syndrome to monitor their symptoms while taking methamphetamine.[22] Due to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.[22]

Side 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 society.[30]

Physical

The physical effects of methamphetamine can includeloss of appetite, hyperactivity,dilated pupils,flushed skin,excessive sweating,increased movement, dry mouth andteeth grinding (leading to "meth mouth"), headache,irregular heartbeat (usually asaccelerated heartbeat orslowed heartbeat),rapid breathing,high blood pressure,low blood pressure,high body temperature, diarrhea, constipation,blurred vision,dizziness,twitching,numbness,tremors, dry skin,acne, andpale appearance.[22][31] Long-term meth users may havesores on their skin;[32][33][34] these may be caused by scratching due toitchiness[33] or the belief that insects are crawling under their skin,[32] and the damage is compounded by poor diet and hygiene.[34] Numerous deaths related to methamphetamine overdoses have also been reported as well.[35][36]

Meth mouth

Main article:Meth mouth
A suspected case ofmeth mouth

Methamphetamine users and addicts may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known asmeth mouth.[37] The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it.[37] According to theAmerican Dental Association, meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting inxerostomia (dry mouth), extended periods of poororal hygiene, frequent consumption of high-calorie, carbonated beverages andbruxism (teeth grinding and clenching)".[37][38] 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.[23]

Sexually transmitted infection

Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in bothHIV-positive and unknown casual partners, an association more pronounced in HIV-positive participants.[39] 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.[39] Methamphetamine use allows users of both sexes to engage in prolonged sexual activity, which may cause genital sores and abrasions as well aspriapism in men.[22][40] Methamphetamine may also cause sores and abrasions in the mouth viabruxism, increasing the risk of sexually transmitted infection.[22][40]

Besides the sexual transmission of HIV, it may also be transmitted between users whoshare a common needle.[41] The level of needle sharing among methamphetamine users is similar to that among other drug injection users.[41]

Death

Doses of 200 mg or more of methamphetamine are considered fatal.[42]

Psychological

The psychological effects of methamphetamine can includeeuphoria,dysphoria, changes inlibido,alertness, apprehension andconcentration, decreased sense of fatigue,insomnia orwakefulness,self-confidence, sociability, irritability, restlessness,grandiosity andrepetitive and obsessive behaviors.[22][31][43] Peculiar to methamphetamine and related stimulants is "punding", persistent non-goal-directed repetitive activity.[44] Methamphetamine use also has a high association withanxiety,depression,amphetamine psychosis,suicide, and violent behaviors.[45]

Neurotoxic

This diagram depicts theneuroimmune mechanisms that mediate methamphetamine-induced neurodegeneration in the human brain.[46] TheNF-κB-mediated neuroimmune response to methamphetamine use which results in the increased permeability of theblood–brain barrier arises through its binding at and activation ofsigma receptors, the increased production ofreactive oxygen species (ROS),reactive nitrogen species (RNS), anddamage-associated molecular pattern molecules (DAMPs), the dysregulation ofglutamate transporters (specifically,EAAT1 andEAAT2) andglucose metabolism, and excessiveCa2+ ion influx inglial cells and dopamineneurons.[46][47][48]

Methamphetamine is directlyneurotoxic to dopaminergic neurons in both lab animals and humans.[49][50]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 ofParkinson'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 toserotonergic neurons.[50] 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 topost-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 adverseneuroplastic changes in brain structure and function.[50] In particular, methamphetamine appears to causehyperintensity andhypertrophy ofwhite matter, marked shrinkage ofhippocampi, and reducedgray matter in thecingulate cortex,limbic cortex, andparalimbic cortex in recreational methamphetamine users.[50] Moreover, evidence suggests that adverse changes in the level ofbiomarkers of metabolic integrity and synthesis occur in recreational users, such as a reduction inN-acetylaspartate andcreatine levels and elevated levels ofcholine andmyoinositol.[50]

Methamphetamine has been shown to activateTAAR1 in humanastrocytes and generatecAMP as a result.[54] Activation of astrocyte-localized TAAR1 appears to function as a mechanism by which methamphetamine attenuates membrane-boundEAAT2 (SLC1A2) levels and function in these cells.[54]

Methamphetamine binds to and activates bothsigma receptor subtypes,σ1 andσ2, with micromolar affinity.[48][56] Sigma receptor activation may promote methamphetamine-induced neurotoxicity by facilitatinghyperthermia, increasing dopamine synthesis and release, influencing microglial activation, and modulatingapoptotic signaling cascades and the formation of reactive oxygen species.[48][56]

Addictive

Addiction and dependence glossary[57][58][59][60]
  • addiction – abiopsychosocial 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 brainreward systems
  • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
  • drug sensitization orreverse 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 anddelirium tremens)
  • psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g.,dysphoria andanhedonia)
  • 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 thenucleus accumbens that results in psychostimulant addiction
The image above contains clickable links
This diagram depicts the signaling events in thebrain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, likeamphetamine, methamphetamine, andphenethylamine. Following presynapticdopamine andglutamateco-release by such psychostimulants,[61][62]postsynaptic receptors for theseneurotransmitters trigger internal signaling events through acAMP-dependent pathway and acalcium-dependent pathway that ultimately result in increasedCREB phosphorylation.[61][63][64] Phosphorylated CREB increases levels of ΔFosB, which in turn represses thec-Fos gene with the help ofcorepressors;[61][65][66]c-Fosrepression 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 for1–2 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-relatedstructural 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 ingene expression in certain parts of the brain, particularly thenucleus accumbens.[68][69] The most importanttranscription factors[note 2] that produce these alterations areΔFosB,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 inD1-typemedium spiny neurons in the nucleus accumbens isnecessary and sufficient[note 3] 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 toalcohol,cannabinoids,cocaine,methylphenidate,nicotine,opioids,phencyclidine,propofol, andsubstituted amphetamines, among others.[69][71][72][73][74]

ΔJunD, a transcription factor, andG9a, ahistone 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 withviral 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 tonatural rewards, such as palatable food, sex, and exercise.[69][72][76] Since both natural rewards and addictive drugsinduce 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-inducedsex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[note 4][72][77] These sex addictions (i.e., drug-induced compulsive sexual behaviors) are associated with adopamine dysregulation syndrome which occurs in some patients takingdopaminergic 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 ingene expression may occur in particular regions of the brain, and may contribute importantly to the addiction phenotype. Recently a crucial role has been found forepigenetic 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 brainreward pathways, including areas likeventral tegmental area,nucleus accumbens, and dorsalstriatum, thehippocampus, and theprefrontal cortex. Chronic methamphetamine use caused gene-specifichistone acetylations, deacetylations andmethylations. Gene-specific DNA methylations in particular regions of the brain were also observed. The various epigenetic alterations causeddownregulations or upregulations of specific genes important in addiction. For instance, chronic methamphetamine use causedmethylation of the lysine in position 4 of histone 3 located at thepromoters of thec-fos and theC-C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens (NAc).[81] c-fos is well known to be important inaddiction.[82] Theccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.[81]

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

Treatment and management

Further information:Addiction § Research

A 2018 systematic review andnetwork meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found thatcombination therapy with bothcontingency management andcommunity reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).[85] Other treatment modalities examined in the analysis includedmonotherapy 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.[85]

As of December 2019[update], there is no effectivepharmacotherapy for methamphetamine addiction.[86][87][88] A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for amphetamine and methamphetamine addiction;[87] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.[87] 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, andmodafinil.[87]

Dependence and withdrawal

Tolerance is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly.[89][90] In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.[91]Depression from methamphetamine withdrawal lasts longer and is more severe than that ofcocaine withdrawal.[92]

According to the current Cochrane review ondrug dependence andwithdrawal 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".[91] 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.[91] Methamphetamine withdrawal symptoms can include anxiety,drug craving,dysphoric mood,fatigue,increased appetite,increased movement ordecreased movement,lack of motivation,sleeplessness orsleepiness, andvivid or lucid dreams.[91]

Methamphetamine that is present in a mother'sbloodstream can pass through theplacenta to afetus and be secreted intobreast milk.[92] Infants born to methamphetamine-abusing mothers may experience aneonatal withdrawal syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, andhypertonia.[92] This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.[92]

Summary of addiction-related plasticity
Form ofneuroplasticity
orbehavioral plasticity		Type ofreinforcerSources
OpiatesPsychostimulantsHigh fat or sugar foodSexual intercoursePhysical exercise
(aerobic)		Environmental
enrichment
ΔFosB expression in
nucleus accumbensD1-typeMSNs		↑↑↑↑↑↑[72]
Behavioral plasticity
Escalation of intakeYesYesYes[72]
Psychostimulant
cross-sensitization		YesNot applicableYesYesAttenuatedAttenuated[72]
Psychostimulant
self-administration		↑↑↓↓↓[72]
Psychostimulant
conditioned place preference		↑↑↓↑↓↑[72]
Reinstatement of drug-seeking behavior↑↑↓↓[72]
Neurochemical plasticity
CREBphosphorylation
in thenucleus accumbens		↓↓↓↓↓[72]
Sensitizeddopamine response
in thenucleus accumbens		NoYesNoYes[72]
Alteredstriataldopamine signaling↓DRD2, ↑DRD3↑DRD1, ↓DRD2, ↑DRD3↑DRD1, ↓DRD2, ↑DRD3↑DRD2↑DRD2[72]
Altered striatalopioid signalingNo change or
↑μ-opioid receptors		↑μ-opioid receptors
↑κ-opioid receptors		↑μ-opioid receptors↑μ-opioid receptorsNo changeNo change[72]
Changes in striatalopioid peptides↑dynorphin
No change:enkephalin		↑dynorphin↓enkephalin↑dynorphin↑dynorphin[72]
Mesocorticolimbicsynaptic plasticity
Number ofdendrites in thenucleus accumbens↓↑↑[72]
Dendritic spine density in
thenucleus accumbens		↓↑↑[72]

Neonatal

Unlike other drugs, babies with prenatal exposure to methamphetamines don't show immediate signs of withdrawal. Instead, cognitive and behavioral problems start emerging when the children reach school age.[93]

Aprospective 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 ofexternalizing andattention deficit/hyperactivity disorders.[94]

Overdose

See also:Aimo Koivunen

A methamphetamine overdose may result in a wide range of symptoms.[11][22] 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, severeagitation,rapid breathing,tremor,urinary hesitancy, andan inability to pass urine.[11][31] An extremely large overdose may produce symptoms such asadrenergic 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 ofstereotypy ("tweaking").[sources 1] A methamphetamine overdose will likely also result in mildbrain damage due todopaminergic andserotonergic neurotoxicity.[98][50] Death from methamphetamine poisoning is typically preceded by convulsions andcoma.[22]

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, anddelusions).[11][99] ACochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine use-induced psychosis states that about 5–15% of users fail to recover completely.[99][100] The same review asserts that, based upon at least one trial,antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[99]Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[101]

Treatment

Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration ofactivated charcoal andsedation.[11] There is not enough evidence onhemodialysis orperitoneal dialysis in cases of methamphetamine intoxication to determine their usefulness.[22]Forced acid diuresis (e.g., withvitamin C) will increase methamphetamine excretion but is not recommended as it may increase the risk of aggravating acidosis, or cause seizures or rhabdomyolysis.[11] Hypertension presents a risk forintracranial hemorrhage (i.e., bleeding in the brain) and, if severe, is typically treated with intravenousphentolamine ornitroprusside.[11] Blood pressure often drops gradually following sufficient sedation with abenzodiazepine and providing a calming environment.[11]

Antipsychotics such ashaloperidol are useful in treating agitation and psychosis from methamphetamine overdose.[102][103]Beta blockers with lipophilic properties and CNS penetration such asmetoprolol andlabetalol may be useful for treating CNS and cardiovascular toxicity.[104] The mixedalpha- andbeta-blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.[102] The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.[102]

Interactions

Methamphetamine is metabolized by the liver enzymeCYP2D6, soCYP2D6 inhibitors will prolong theelimination half-life of methamphetamine.[105] Methamphetamine also interacts withmonoamine oxidase inhibitors (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.[22] Methamphetamine may decrease the effects ofsedatives anddepressants and increase the effects ofantidepressants and otherstimulants as well.[22] Methamphetamine may counteract the effects ofantihypertensives andantipsychotics due to its effects on the cardiovascular system and cognition respectively.[22] ThepH of gastrointestinal content and urine affects the absorption and excretion of methamphetamine.[22] Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite.[22] Due to the effect pH has on absorption,proton pump inhibitors, which reducegastric acid, are known to interact with methamphetamine.[22]

Pharmacology

An image of methamphetamine pharmacodynamics
This illustration depicts the normal operation of thedopaminergic 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 activatingTAAR1 (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 potentfull agonist oftrace amine-associated receptor 1 (TAAR1), aG protein-coupled receptor (GPCR) that regulates braincatecholamine systems.[106][107] Activation of TAAR1 increasescyclic adenosine monophosphate (cAMP) production and either completely inhibits or reverses the transport direction of thedopamine transporter (DAT),norepinephrine transporter (NET), andserotonin transporter (SERT).[106][108] When methamphetamine binds to TAAR1, it triggers transporterphosphorylation viaprotein kinase A (PKA) andprotein kinase C (PKC) signaling, ultimately resulting in theinternalization or reverse function ofmonoamine transporters.[106][109] Methamphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through aCa2+/calmodulin-dependent protein kinase (CAMK)-dependent signaling pathway, in turn producing dopamine efflux.[110][111][112] TAAR1 has been shown to reduce thefiring rate of neurons through direct activation ofG protein-coupled inwardly-rectifying potassium channels.[113][114][115] TAAR1 activation by methamphetamine inastrocytes appears to negatively modulate the membrane expression and function ofEAAT2, a type ofglutamate transporter.[54]

In addition to its effect on the plasma membrane monoamine transporters, methamphetamine inhibits synaptic vesicle function by inhibitingVMAT2, which prevents monoamine uptake into the vesicles and promotes their release.[116] This results in the outflow of monoamines fromsynaptic vesicles into thecytosol (intracellular fluid) of thepresynaptic neuron, and their subsequent release into the synaptic cleft by the phosphorylated transporters.[117] Othertransporters that methamphetamine is known to inhibit areSLC22A3 andSLC22A5.[116] SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinitycarnitine transporter.[107][118]

Methamphetamine is also anagonist of thealpha-2 adrenergic receptors andsigma receptors with a greateraffinity forσ1 thanσ2, and inhibitsmonoamine oxidase A (MAO-A) andmonoamine oxidase B (MAO-B).[48][107][56] Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain.[48][56] Dextromethamphetamine is a strongerpsychostimulant, butlevomethamphetamine has strongerperipheral effects, a longer half-life, and longer perceived effects among addicts.[119][120][121] At high doses, both enantiomers of methamphetamine can induce similarstereotypy andmethamphetamine psychosis,[120] but levomethamphetamine has shorter psychodynamic effects.[121]

Pharmacokinetics

Following oral administration, methamphetamine is well-absorbed into the bloodstream, with peak plasma methamphetamine concentrations achieved in approximately 3.13–6.3 hours post ingestion.[122] Methamphetamine is also well absorbed following inhalation and following intranasal administration.[11] Due to the high lipophilicity of methamphetamine, it can readily move through theblood–brain barrier faster than other stimulants, where it is more resistant to degradation bymonoamine oxidase.[11][122] The amphetamine metabolite peaks at 10–24 hours.[11] Methamphetamine is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH.[22][122] When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine.[122] Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine.[122] Thehalf-life of methamphetamine is variable with a range of 5–30 hours.[11]

CYP2D6,dopamine β-hydroxylase,flavin-containing monooxygenase 3,butyrate-CoA ligase, andglycine N-acyltransferase are the enzymes known to metabolize methamphetamine or its metabolites in humans.[sources 2] The primary metabolites are amphetamine and4-hydroxymethamphetamine;[122] other minor metabolites include:4-hydroxyamphetamine,4-hydroxynorephedrine,4-hydroxyphenylacetone,benzoic acid,hippuric acid,norephedrine, andphenylacetone, the metabolites of amphetamine.[8][122][123] Among these metabolites, the activesympathomimetics are amphetamine,4‑hydroxyamphetamine,[129]4‑hydroxynorephedrine,[130]4-hydroxymethamphetamine,[122] and norephedrine.[131] Methamphetamine is a CYP2D6 inhibitor.[105]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[8][122][132] The known metabolic pathways include:

Metabolic pathways of methamphetamine in humans[sources 2]
The image above contains clickable links
The primary metabolites of methamphetamine are amphetamine and 4-hydroxymethamphetamine.[122]Human microbiota, particularlyLactobacillus,Enterococcus, andClostridium species, contribute to the metabolism of methamphetamine via an enzyme which N-demethylates methamphetamine and 4-hydroxymethamphetamine into amphetamine and 4-hydroxyamphetamine respectively.[133][134]

Detection in biological fluids

Methamphetamine and amphetamine are often measured in urine or blood as part of adrug test for sports, employment, poisoning diagnostics, and forensics.[135][136][137][138] 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.[139] Chiral separation is needed to assess the possible contribution oflevomethamphetamine, which is an active ingredients in some OTC nasal decongestants, toward a positive test result.[139][140][141] Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.[142]

Chemistry

Methamphetamine hydrochloride
Shards of pure methamphetamine hydrochloride, also known as crystal meth

Methamphetamine is achiral compound with two enantiomers, dextromethamphetamine and levomethamphetamine. At room temperature, thefree base of methamphetamine is a clear and colorless liquid with an odor characteristic ofgeranium leaves.[12] It issoluble indiethyl ether andethanol as well asmiscible withchloroform.[12]

In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste.[12] It has a melting point between 170 and 175 °C (338 and 347 °F) and, at room temperature, occurs as white crystals or a whitecrystalline powder.[12] The hydrochloride salt is also freely soluble in ethanol and water.[12] Its crystal structure ismonoclinic with P21space group; at 90 K (−183.2 °C; −297.7 °F), it haslattice parametersa = 7.10 Å,b = 7.29 Å,c = 10.81 Å, andβ = 97.29°.[143]

Degradation

A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration.[144] A year-long study (also from 2011) showed that methamphetamine in soils is a persistent pollutant.[145] In a 2013 study of bioreactors inwastewater, methamphetamine was found to be largely degraded within 30 days under exposure to light.[146]

Synthesis

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

Racemic methamphetamine may be prepared starting fromphenylacetone by either theLeuckart[147] orreductive amination methods.[148] In the Leuckart reaction, one equivalent of phenylacetone is reacted with two equivalents ofN-methylformamide to produce the formylamide of methamphetamine plus carbon dioxide andmethylamine as side products.[148] In this reaction, animinium cation is formed as an intermediate which isreduced by the second equivalent ofN-methylformamide.[148] The intermediate formyl amide is thenhydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product.[148] Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.[148]

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

History

Main article:History and culture of substituted amphetamines
A methamphetamine tablet container
Pervitin, a methamphetamine brand used by German soldiers duringWorld 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).[149][150]

Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemistLazăr Edeleanu who named itphenylisopropylamine.[151][152] Shortly after, methamphetamine was synthesized fromephedrine in 1893 by JapanesechemistNagai Nagayoshi.[153] Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologistAkira Ogata viareduction of ephedrine using redphosphorus andiodine.[154]

Since 1938, methamphetamine was marketed on a large scale in Germany as a nonprescription drug under the brand namePervitin, produced by the Berlin-basedTemmler pharmaceutical company.[155][156] It was used by all branches of the combinedWehrmacht armed forces of theThird Reich, for its stimulant effects and to induce extendedwakefulness.[157][158] Pervitin became colloquially known among the German troops as "Stuka-Tablets" (Stuka-Tabletten) and "Herman-Göring-Pills" (Hermann-Göring-Pillen). Side effects were so serious that the army sharply cut back its usage in 1940.[159] By 1941, usage was restricted to a doctor's prescription, and the military tightly controlled its distribution. Soldiers would only receive a couple 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 very violent, committing war crimes against civilians; others attacked their own officers.[159]

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 ofobesity, was one of the first brands of pharmaceutical methamphetamine products.[160] Due to the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s.[160] Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.[152] For example, during the early 1970s in the United States, methamphetamine became aschedule II controlled substance under theControlled Substances Act.[161] Currently, methamphetamine is sold under the trade nameDesoxyn,trademarked by the Danish pharmaceutical companyLundbeck.[162] As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.[163]

Society and culture

Trafficking

TheGolden Triangle (Southeast Asia), specificallyShan State, Myanmar, is the world's leading producer of methamphetamine as production has shifted toYaba and crystalline methamphetamine, including for export to the United States and across East and Southeast Asia and the Pacific.[164]

Concerning the accelerating synthetic drug production in the region, the Cantonese Chinese syndicateSam Gor, also known as The Company, is understood to be the main international crime syndicate responsible for this shift.[165] 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.[166] Sam Gor is alleged to control 40% of the Asia-Pacific methamphetamine market, while also traffickingheroin andketamine. 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 theGolden Triangle, specifically Shan State, Myanmar, responsible for much of the massive surge of crystal meth in recent years.[167] The group is understood to be headed byTse Chi Lop, a gangster born inGuangzhou,China who also holds a Canadian passport.

Legal status

Main article:Legal status of methamphetamine

The production, distribution, sale, and possession of methamphetamine is restricted or illegal in manyjurisdictions.[168][169] Methamphetamine has been placed in schedule II of theUnited NationsConvention on Psychotropic Substances treaty.[169]

Research

It has been suggested, based on animal research, that calcitriol, the active metabolite ofvitamin D, can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of methamphetamine.[170]

See also

Explanatory notes

  1. ↑Synonyms and brands include:N-methylamphetamine, desoxyephedrine, Syndrox, Methedrine, and Desoxyn.[1][13][14] Slang terms include: speed, crank, meth, crystal meth, pervitin, yaba, and shabu
  2. ↑Transcription factors are proteins that increase or decrease theexpression of specific genes.[70]
  3. ↑In simpler terms, thisnecessary 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.
  4. ↑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. ↑
      (Text color)Transcription factors

Reference notes

  1. ↑[11][22][31][43][95][96][97]
  2. ↑2.02.1[7][8][9][10][122][123][124][125][126][127][128]

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  48. ↑48.048.148.248.348.4Kaushal N, Matsumoto RR (March 2011)."Role of sigma receptors in methamphetamine-induced neurotoxicity".Curr Neuropharmacol.9 (1): 54–57.doi:10.2174/157015911795016930.PMC 3137201.PMID 21886562.σ Receptors seem to play an important role in many of the effects of METH. They are present in the organs that mediate the actions of METH (e.g. brain, heart, lungs) [5]. In the brain, METH acts primarily on the dopaminergic system to cause acute locomotor stimulant, subchronic sensitized, and neurotoxic effects. σ Receptors are present on dopaminergic neurons and their activation stimulates dopamine synthesis and release [11–13]. σ-2 Receptors modulate DAT and the release of dopamine via protein kinase C (PKC) and Ca2+-calmodulin systems [14].
    σ-1 Receptor antisense and antagonists have been shown to block the acute locomotor stimulant effects of METH [4]. Repeated administration or self administration of METH has been shown to upregulate σ-1 receptor protein and mRNA in various brain regions including the substantia nigra, frontal cortex, cerebellum, midbrain, and hippocampus [15, 16]. Additionally, σ receptor antagonists ... prevent the development of behavioral sensitization to METH [17, 18]. ...
    σ Receptor agonists have been shown to facilitate dopamine release, through both σ-1 and σ-2 receptors [11–14].
  49. ↑Yu S, Zhu L, Shen Q, Bai X, Di X (2015)."Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology".Behav Neurol.2015: 1–11.doi:10.1155/2015/103969.PMC 4377385.PMID 25861156.
  50. ↑50.050.150.250.350.450.5Krasnova IN, Cadet JL (May 2009)."Methamphetamine toxicity and messengers of death".Brain Res. Rev.60 (2): 379–407.doi:10.1016/j.brainresrev.2009.03.002.PMC 2731235.PMID 19328213.Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...
    Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ...
    There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ...
    Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007).
  51. ↑Yu S, Zhu L, Shen Q, Bai X, Di X (2015)."Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology".Behavioural Neurology.2015: 103969.doi:10.1155/2015/103969.PMC 4377385.PMID 25861156.
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     • Jing L, Li JX (August 2015)."Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction".Eur. J. Pharmacol.761: 345–352.doi:10.1016/j.ejphar.2015.06.019.PMC 4532615.PMID 26092759.TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007)
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  56. ↑56.056.156.256.3Rodvelt KR, Miller DK (September 2010). "Could sigma receptor ligands be a treatment for methamphetamine addiction?".Curr Drug Abuse Rev.3 (3): 156–162.doi:10.2174/1874473711003030156.PMID 21054260.
  57. ↑Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375.ISBN 9780071481274.
  58. ↑58.058.158.258.3Nestler EJ (December 2013)."Cellular basis of memory for addiction".Dialogues in Clinical Neuroscience.15 (4): 431–443.PMC 3898681.PMID 24459410.Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
  59. ↑"Glossary of Terms".Mount Sinai School of Medicine. Department of Neuroscience. Retrieved9 February 2015.
  60. ↑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.
  61. ↑61.061.161.2Renthal 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 andc-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg,c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
    Figure 2: Psychostimulant-induced signaling events
  62. ↑Broussard JI (January 2012)."Co-transmission of dopamine and glutamate".The Journal of General Physiology.139 (1): 93–96.doi:10.1085/jgp.201110659.PMC 3250102.PMID 22200950.Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.
  63. ↑Kanehisa Laboratories (10 October 2014)."Amphetamine – Homo sapiens (human)".KEGG Pathway. Retrieved31 October 2014.Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
  64. ↑Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015)."Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat".Molecular Neurobiology.51 (2): 696–717.doi:10.1007/s12035-014-8776-8.PMC 4359351.PMID 24939695.Figure 1{{cite journal}}:External link in|quote= (help)
  65. ↑65.065.165.2Robison AJ, Nestler EJ (November 2011)."Transcriptional and epigenetic mechanisms of addiction".Nature Reviews Neuroscience.12 (11): 623–637.doi:10.1038/nrn3111.PMC 3272277.PMID 21989194.ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to thec-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result isc-fos gene repression.
    Figure 4: Epigenetic basis of drug regulation of gene expression
  66. ↑66.066.166.2Nestler EJ (December 2012)."Transcriptional mechanisms of drug addiction".Clinical Psychopharmacology and Neuroscience.10 (3): 136–143.doi:10.9758/cpn.2012.10.3.136.PMC 3569166.PMID 23430970.The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress thec-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
  67. ↑Nestler EJ (October 2008)."Transcriptional mechanisms of addiction: Role of ΔFosB".Philosophical Transactions of the Royal Society B: Biological Sciences.363 (1507): 3245–3255.doi:10.1098/rstb.2008.0067.PMC 2607320.PMID 18640924.Recent evidence has shown that ΔFosB also represses thec-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
  68. ↑Hyman SE, Malenka RC, Nestler EJ (July 2006)."Neural mechanisms of addiction: the role of reward-related learning and memory"(PDF).Annu. Rev. Neurosci.29: 565–598.doi:10.1146/annurev.neuro.29.051605.113009.PMID 16776597.S2CID 15139406. Archived fromthe original(PDF) on 2018-09-19.Archived 2018-09-19 at theWayback Machine
  69. ↑69.069.169.269.369.469.569.669.7Robison AJ, Nestler EJ (November 2011)."Transcriptional and epigenetic mechanisms of addiction".Nat. Rev. Neurosci.12 (11): 623–637.doi:10.1038/nrn3111.PMC 3272277.PMID 21989194.ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant-negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high-fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
  70. ↑Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 4: Signal Transduction in the Brain". In Sydor A, Brown RY (eds.).Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 94.ISBN 978-0-07-148127-4.
  71. ↑71.071.171.2Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?".Am. J. Drug Alcohol Abuse.40 (6): 428–437.doi:10.3109/00952990.2014.933840.PMID 25083822.S2CID 19157711.ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
  72. ↑72.0072.0172.0272.0372.0472.0572.0672.0772.0872.0972.1072.1172.1272.1372.1472.1572.1672.17Olsen CM (December 2011)."Natural rewards, neuroplasticity, and non-drug addictions".Neuropharmacology.61 (7): 1109–1122.doi:10.1016/j.neuropharm.2011.03.010.PMC 3139704.PMID 21459101.Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).
  73. ↑Kanehisa Laboratories (29 October 2014)."Alcoholism – Homo sapiens (human)".KEGG Pathway.Archived from the original on 13 October 2014. Retrieved31 October 2014.Archived 13 October 2014 at theWayback Machine
  74. ↑Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009)."Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens".Proc. Natl. Acad. Sci. U.S.A.106 (8): 2915–2920.Bibcode:2009PNAS..106.2915K.doi:10.1073/pnas.0813179106.PMC 2650365.PMID 19202072.
  75. ↑Nestler EJ (January 2014)."Epigenetic mechanisms of drug addiction".Neuropharmacology. 76 Pt B: 259–268.doi:10.1016/j.neuropharm.2013.04.004.PMC 3766384.PMID 23643695.
  76. ↑76.076.1Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (March 2012)."Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms".Journal of Psychoactive Drugs.44 (1): 38–55.doi:10.1080/02791072.2012.662112.PMC 4040958.PMID 22641964.It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. ... these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.
  77. ↑77.077.1Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013)."Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator".J. Neurosci.33 (8): 3434–3442.doi:10.1523/JNEUROSCI.4881-12.2013.PMC 3865508.PMID 23426671.Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity
  78. ↑Brecht ML, Herbeck D (June 2014)."Time to relapse following treatment for methamphetamine use: a long-term perspective on patterns and predictors".Drug Alcohol Depend.139: 18–25.doi:10.1016/j.drugalcdep.2014.02.702.PMC 4550209.PMID 24685563.
  79. ↑Brecht ML, Lovinger K, Herbeck DM, Urada D (2013)."Patterns of treatment utilization and methamphetamine use during first 10 years after methamphetamine initiation".J Subst Abuse Treat.44 (5): 548–56.doi:10.1016/j.jsat.2012.12.006.PMC 3602162.PMID 23313146.
  80. ↑Nestler EJ (January 2014)."Epigenetic mechanisms of drug addiction".Neuropharmacology. 76 Pt B: 259–68.doi:10.1016/j.neuropharm.2013.04.004.PMC 3766384.PMID 23643695.
  81. ↑81.081.181.2Godino A, Jayanthi S, Cadet JL (2015)."Epigenetic landscape of amphetamine and methamphetamine addiction in rodents".Epigenetics.10 (7): 574–80.doi:10.1080/15592294.2015.1055441.PMC 4622560.PMID 26023847.
  82. ↑Cruz FC, Javier Rubio F, Hope BT (December 2015)."Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction".Brain Res.1628 (Pt A): 157–73.doi:10.1016/j.brainres.2014.11.005.PMC 4427550.PMID 25446457.
  83. ↑Jayanthi S, McCoy MT, Chen B, Britt JP, Kourrich S, Yau HJ, Ladenheim B, Krasnova IN, Bonci A, Cadet JL (July 2014)."Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms".Biol. Psychiatry.76 (1): 47–56.doi:10.1016/j.biopsych.2013.09.034.PMC 3989474.PMID 24239129.
  84. ↑Kenny PJ, Markou A (May 2004). "The ups and downs of addiction: role of metabotropic glutamate receptors".Trends Pharmacol. Sci.25 (5): 265–72.doi:10.1016/j.tips.2004.03.009.PMID 15120493.
  85. ↑85.085.1De Crescenzo F, Ciabattini M, D'Alò GL, De Giorgi R, Del Giovane C, Cassar C, Janiri L, Clark N, Ostacher MJ, Cipriani A (December 2018)."Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis".PLOS Medicine.15 (12): e1002715.doi:10.1371/journal.pmed.1002715.PMC 6306153.PMID 30586362.
  86. ↑Stoops WW, Rush CR (May 2014)."Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research".Expert Rev Clin Pharmacol.7 (3): 363–374.doi:10.1586/17512433.2014.909283.PMC 4017926.PMID 24716825.Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.
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  88. ↑Forray A, Sofuoglu M (February 2014)."Future pharmacological treatments for substance use disorders".Br. J. Clin. Pharmacol.77 (2): 382–400.doi:10.1111/j.1365-2125.2012.04474.x.PMC 4014020.PMID 23039267.
  89. ↑O'Connor P."Amphetamines: Drug Use and Abuse".Merck Manual Home Health Handbook. Merck.Archived from the original on 17 February 2007. Retrieved26 September 2013.Archived 17 February 2007 at theWayback Machine
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  91. ↑91.091.191.291.3Shoptaw SJ, Kao U, Heinzerling K, Ling W (2009). Shoptaw SJ (ed.)."Treatment for amphetamine withdrawal".Cochrane Database Syst. Rev. (2): CD003021.doi:10.1002/14651858.CD003021.pub2.PMC 7138250.PMID 19370579.The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005)
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  94. ↑LaGasse LL, Derauf C, Smith LM, Newman E, Shah R, Neal C, et al. (April 2012)."Prenatal methamphetamine exposure and childhood behavior problems at 3 and 5 years of age".Pediatrics. American Academy of Pediatrics.129 (4): 681–8.doi:10.1542/peds.2011-2209.PMC 3313637.PMID 22430455.
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  99. ↑99.099.199.2Shoptaw SJ, Kao U, Ling W (2009). Shoptaw SJ, Ali R (eds.)."Treatment for amphetamine psychosis".Cochrane Database Syst. Rev. (1): CD003026.doi:10.1002/14651858.CD003026.pub3.PMC 7004251.PMID 19160215.A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
    About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
    Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
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  122. ↑122.00122.01122.02122.03122.04122.05122.06122.07122.08122.09122.10"Pharmacology".Methamphetamine.DrugBank. University of Alberta. 2 October 2017.Archived from the original on 6 October 2017. Retrieved5 October 2017.Methamphetamine is rapidly absorbed from the gastrointestinal tract with peak methamphetamine concentrations occurring in 3.13 to 6.3 hours post ingestion. Methamphetamine is also well absorbed following inhalation and following intranasal administration. It is distributed to most parts of the body. Because methamphetamine has a high lipophilicity it is distributed across the blood brain barrier and crosses the placenta. ...
    The primary site of metabolism is in the liver by aromatic hydroxylation, N-dealkylation and deamination. At least seven metabolites have been identified in the urine, with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine. Other minor metabolites include 4-hydroxyamphetamine, norephedrine, and 4-hydroxynorephedrine.
  123. ↑123.0123.1Santagati 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.
  124. ↑Glennon RA (2013)."Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.).Foye's principles of medicinal chemistry (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648.ISBN 978-1-60913-345-0.Archived from the original on 2020-07-26. Retrieved2021-10-25.The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation top-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affordsp-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
  125. ↑Taylor KB (January 1974)."Dopamine-beta-hydroxylase. Stereochemical course of the reaction"(PDF).J. Biol. Chem.249 (2): 454–458.doi:10.1016/S0021-9258(19)43051-2.PMID 4809526.Archived(PDF) from the original on 7 October 2018. Retrieved6 November 2014.Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.Archived 7 October 2018 at theWayback Machine
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  137. ↑Kraemer T, Paul LD (August 2007). "Bioanalytical procedures for determination of drugs of abuse in blood".Anal. Bioanal. Chem.388 (7): 1415–1435.doi:10.1007/s00216-007-1271-6.PMID 17468860.S2CID 32917584.
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  139. ↑139.0139.1Paul BD, Jemionek J, Lesser D, Jacobs A, Searles DA (September 2004)."Enantiomeric separation and quantitation of (+/-)-amphetamine, (+/-)-methamphetamine, (+/-)-MDA, (+/-)-MDMA, and (+/-)-MDEA in urine specimens by GC-EI-MS after derivatization with (R)-(−)- or (S)-(+)-alpha-methoxy-alpha-(trifluoromethy)phenylacetyl chloride (MTPA)".J. Anal. Toxicol.28 (6): 449–455.doi:10.1093/jat/28.6.449.PMID 15516295.
  140. ↑de la Torre R, Farré M, Navarro M, Pacifici R, Zuccaro P, Pichini S (2004). "Clinical pharmacokinetics of amfetamine and related substances: monitoring in conventional and non-conventional matrices".Clin Pharmacokinet.43 (3): 157–185.doi:10.2165/00003088-200443030-00002.PMID 14871155.S2CID 44731289.
  141. ↑Baselt RC (2020).Disposition of toxic drugs and chemicals in man. Seal Beach, Ca.: Biomedical Publications. pp. 1277–1280.ISBN 978-0-578-57749-4.
  142. ↑Venkatratnam A, Lents NH (July 2011)."Zinc reduces the detection of cocaine, methamphetamine, and THC by ELISA urine testing".J. Anal. Toxicol.35 (6): 333–340.doi:10.1093/anatox/35.6.333.PMID 21740689.
  143. ↑Hakey P, Ouellette W, Zubieta J, Korter T (April 2008)."Redetermination of (+)-methamphetamine hydro-chloride at 90 K".Acta Crystallographica Section E.64 (Pt 5): o940.doi:10.1107/S1600536808011550.PMC 2961146.PMID 21202421.
  144. ↑Nakayama, MT."Chemical Interaction of Bleach and Methamphetamine: A Study of Degradation and Transformation Effects".gradworks. UNIVERSITY OF CALIFORNIA, DAVIS.Archived from the original on 19 October 2014. Retrieved17 October 2014.Archived 19 October 2014 at theWayback Machine
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