Methamphetamine

Methamphetamine
INN: Metamfetamine
Clinical data
Pronunciation	/ˌmɛθæmˈfɛtəmiːn/; (METH-am-FET-ə-meen), /ˌmɛθəmˈfɛtəmiːn/; (METH-əm-FET-ə-meen), /ˌmɛθəmˈfɛtəmən/; (METH-əm-FET-ə-mən)
Trade names	Desoxyn, Methedrine
Other names	N-methylamphetamine, N,α-dimethylphenethylamine, desoxyephedrine
AHFS/Drugs.com	Monograph
License data	US FDA: Methamphetamine;
Dependence; liability	Physical: None; Psychological: Very High
Addiction; liability	Very High
Routes of; administration	Medical: oral (ingestion); Recreational: oral, intravenous, intramuscular, subcutaneous, vapour inhalation, insufflation, rectal, vaginal
ATC code	N06BA03 (WHO) ;
Legal status
Legal status	AU: S8 (Controlled drug); BR: Class F2 (Prohibited psychotropics); CA: Schedule I; DE: Anlage II (Authorized trade only, not prescriptible); NZ: Class A; UK: Class A; US: Schedule II; UN: Psychotropic Schedule II;
Pharmacokinetic data
Bioavailability	Oral: 67%; Intranasal: 79%; Inhalation: 67–90%; Intravenous: 100%
Protein binding	Varies widely
Metabolism	CYP2D6 and FMO3
Onset of action	Oral: 3 hours (peak); Intranasal: <15 minutes; Inhalation: <18 minutes; Intravenous: <15 minutes
Elimination half-life	9–12 hours (range 5–30 hours) (irrespective of route)
Duration of action	8–12 hours
Excretion	Primarily kidney
Identifiers
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CAS Number	537-46-2 ; (dl)-Methamphetamine hydrochloride: 300-42-5 ;
PubChem CID	1206;
IUPHAR/BPS	4803;
DrugBank	DB01577 ;
ChemSpider	1169 ;
UNII	44RAL3456C; (dl)-Methamphetamine hydrochloride: 24GNZ56D62 ;
KEGG	D08187 ;
ChEBI	CHEBI:6809 ;
ChEMBL	ChEMBL1201201 ;
PDB ligand	B40 (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID8037128 ;
ECHA InfoCard	100.007.882
Chemical and physical data
Formula	C10H15N
Molar mass	149.237 g·mol−1
3D model (JSmol)	Interactive image;
Chirality	Racemic mixture
Melting point	170 °C (338 °F)
Boiling point	212 °C (414 °F) at 760 mmHg
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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 treatmentfor attention deficit hyperactivity disorder and obesity.^[22] Methamphetamine was discovered in 1893 and exists as two enantiomers: levo-methamphetamine and dextro-methamphetamine.^{[note 2]}Methamphetamine properly refers to a specific chemical substance, the racemic free base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms, but the hydrochloride salt, commonly called crystal meth, is widely used. Methamphetamine is rarely prescribed over concerns involving 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. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.

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.^[26]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 and, to a lesser extent, serotonergic neurons at high doses.^[27]^[28]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.^[28]

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

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;^[29]^[30] however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use.^[29] To avoid toxicity and risk of side effects, FDA guidelines recommend an initial dose of methamphetamine at doses 5–10 mg/day for ADHD in adults and children over six years of age, and may be increased at weekly intervals of 5 mg, up to 25 mg/day, until optimum clinical response is found; the usual effective dose is around 20–25 mg/day.^[6]^[29] Methamphetamine is sometimes prescribed off label for narcolepsy and idiopathic hypersomnia.^[31]^[32] In the United States, methamphetamine's levorotary form is available in some over-the-counter (OTC) nasal decongestantproducts.^{[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.^[29] Methamphetamine hydrochloride dispensed in the United States is required to include a boxed warning regarding its potential for recreational misuse and addiction liability.^[29]

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

Recreational

Methamphetamine is often used recreationally for its effects as a potent euphoriant and stimulant as well as aphrodisiac qualities.^[34]

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

Desoxyn 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.^[29] 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.^[29] 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.^[29] Owing to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.^[29]

Adverse effects

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

Physical

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.^[29]^[37] Long-term meth users may have sores on their skin;^[38]^[39] these may be caused by scratching due to itchiness or the belief that insects are crawling under their skin,^[38] and the damage is compounded by poor diet and hygiene.^[39] Numerous deaths related to methamphetamine overdoses have been reported.^[40]^[41]

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.^[42] The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it.^[42] 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)".^[42]^[43] As dry mouth is also a common side effect of other stimulants, which are not known to contribute severe tooth decay, many researchers suggest that methamphetamine-associated tooth decay is more due to users' other choices. They suggest the side effect has been exaggerated and stylized to create a stereotype of current users as a deterrence for new ones.^[30]

Sexually transmitted infection

Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in both HIV-positive and unknown casual partners, an association more pronounced in HIV-positive participants.^[44] 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.^[44] 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.^[29]^[45] Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.^[29]^[45]

Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle.^[46] The level of needle sharing among methamphetamine users is similar to that among other drug injection users.^[46]

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 obsessivebehaviors.^[29]^[37]^[47] Peculiar to methamphetamine and related stimulants is "punding", persistent non-goal-directed repetitive activity.^[48]Methamphetamine use also has a high association with anxiety, depression, amphetamine psychosis, suicide, and violent behaviors.^[49]^[50]

Neurotoxic and neuroimmunological

Methamphetamine is directly neurotoxic to dopaminergic neurons in both lab animals and humans.^[27]^[28] Excitotoxicity, oxidative stress, metabolic compromise, UPS dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression and other processes contributed to this neurotoxicity.^[54]^[55]^[56] In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of Parkinson's disease.^[57] In addition to its dopaminergic neurotoxicity, a review of evidence in humans indicated that high-dose methamphetamine use can also be neurotoxic to serotonergic neurons.^[28] It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.^[58] Withdrawal of methamphetamine in dependent persons may lead to post-acute withdrawal which persists months beyond the typical withdrawal period.^[56]

Magnetic resonance imaging studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse neuroplastic changes in brain structure and function.^[28] In particular, methamphetamine appears to cause hyperintensity and hypertrophyof white matter, marked shrinkage of hippocampi, and reduced gray matter in the cingulate cortex, limbic cortex, and paralimbic cortex in recreational methamphetamine users.^[28]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-acetylaspartateand creatine levels and elevated levels of choline and myoinositol.^[28]

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

Methamphetamine binds to and activates both sigma receptor subtypes, σ₁ and σ₂, with micromolar affinity.^[53]^[59] Sigma receptor activation may promote methamphetamine-induced neurotoxicity by facilitating hyperthermia, increasing dopamine synthesis and release, influencing microglial activation, and modulating apoptotic signaling cascades and the formation of reactive oxygen species.^[53]^[59]

Addictive

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction

The signaling cascade involved in psychostimulant addiction

Note: colored text contains article links.

G_s

cAMP

ΔFosB

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,^[63]^[64] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREBphosphorylation.^[63]^[65]^[66] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fosgene with the help of corepressors;^[63]^[67]^[68] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.^[69] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.^[67]^[68] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.^[67]^[68]

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

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

Epigenetic factors

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

The frequent persistence of addiction suggests that long-lasting changes in gene expression may occur in particular regions of the brain, and may contribute importantly to the addiction phenotype. In 2014, a crucial role was found for epigenetic mechanisms in driving lasting changes in gene expression in the brain.^[82]

A review in 2015^[83] 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).^[83] c-fos is well known to be important in addiction.^[84] The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.^[83]

In methamphetamine addicted rats, epigenetic regulation through reduced acetylation of histones, in brain striatal neurons, caused reduced transcription of glutamate receptors.^[85] Glutamate receptors play an important role in regulating the reinforcing effects of misused illicit drugs.^[86]

Administration of methamphetamine to rodents causes DNA damage in their brain, particularly in the nucleus accumbens region.^[87]^[88] 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.^[89] These alterations can be epigenetic scars in the chromatin that contribute to the persistent epigenetic changes found in methamphetamine addiction.

Treatment and management

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).^[90] 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.^[90]

As of December 2019, there is no effective pharmacotherapy for methamphetamine addiction.^[91]^[92]^[93] A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in randomized controlled trials (RCTs) for amphetamine and methamphetamine addiction;^[92] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.^[92] 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.^[92]^{[verification needed]}

Dependence and withdrawal

Tolerance is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly.^[94]^[95] In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.^[96] Depression from methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.^[97]

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".^[96]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.^[96] 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.^[96]

Methamphetamine that is present in a mother's bloodstream can pass through the placenta to a fetus and be secreted into breast milk.^[97] Infants born to methamphetamine-abusing mothers may experience a neonatal withdrawal syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and hypertonia.^[97] This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.^[97]

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

Neonatal

Unlike other drugs, babies with prenatal exposure to methamphetamine do not show immediate signs of withdrawal. Instead, cognitive and behavioral problems start emerging when the children reach school age.^[98]

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/hyperactivitydisorders.^[99]

Overdose

A methamphetamine overdose may result in a wide range of symptoms.^[4]^[29] 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.^[4]^[37] An extremely large overdose may produce symptoms such as adrenergic storm, methamphetamine psychosis, substantially reduced or no urine output, cardiogenic shock, bleeding in the brain, circulatory collapse, hyperpy rexia (i.e., dangerously high body temperature), pulmonary hypertension, kidney failure, rapid muscle breakdown, serotonin syndrome, and a form of stereotypy ("tweaking").^{[sources 1]} A methamphetamine overdose will likely also result in mild brain damageowing to dopaminergic and serotonergic neurotoxicity.^[103]^[28] Death from methamphetamine poisoning is typically preceded by convulsions and coma.^[29]

Psychosis

Use of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g., paranoia, hallucinations, delirium, and delusions).^[4]^[104] 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.^[104]^[105] The same review asserts that, based upon at least one trial, antipsychoticmedications effectively resolve the symptoms of acute amphetamine psychosis.^[104] Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.^[106]

Death from overdose

Methamphetamine overdose is a diverse term. It frequently refers to the exaggeration of the unusual effects with features such as irritability, agitation, hallucinations and paranoia. It might also refer to intentional self-harm or a fatal outcome. The CDC reported that the number of deaths in the United States involving psychostimulants with abuse potential to be 23,837 in 2020 and 32,537 in 2021.^[107] This category code (ICD–10 of T43.6) includes primarily methamphetamine but also other stimulants such as amphetamine, and methylphenidate. The mechanism of death in these cases is not reported in these statistics and is difficult to know.^[108] Some deaths are as a result of intracranial hemorrhage^[109] and some deaths are cardiovascular in nature including flash pulmonary edema^[110] and ventricular fibrillation.^[111]

Emergency treatment

Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of activated charcoal and sedation.^[4] There is not enough evidence on hemodialysis or peritoneal dialysis in cases of methamphetamine intoxication to determine their usefulness.^[29] 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.^[4] Hypertension presents a risk for intracranial hemorrhage (i.e., bleeding in the brain) and, if severe, is typically treated with intravenous phentolamine or nitroprusside.^[4] Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment.^[4]

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

Interactions

Methamphetamine is metabolized by the liver enzyme CYP2D6, so CYP2D6 inhibitors will prolong the elimination half-life of methamphetamine.^[115]Methamphetamine also interacts with monoamine oxidase inhibitors (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.^[29] Methamphetamine may decrease the effects of sedatives and depressants and increase the effects of antidepressants and other stimulants as well.^[29] Methamphetamine may counteract the effects of antihypertensives and antipsychotics owing to its effects on the cardiovascular system and cognition respectively.^[29] The pH of gastrointestinal content and urine affects the absorption and excretion of methamphetamine.^[29] Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite.^[29] Owing to the effect pH has on absorption, proton pump inhibitors, which reduce gastric acid, are known to interact with methamphetamine.^[29]

Pharmacology

Pharmacodynamics

Methamphetamine has been identified as a potent full agonist of trace amine-associated receptor 1(TAAR1), a G protein-coupled receptor (GPCR) that regulates brain catecholamine systems.^[116]^[117]Activation of TAAR1 increases cyclic adenosine monophosphate (cAMP) production and either completely inhibits or reverses the transport direction of the dopamine transporter (DAT), norepinephrine transporter(NET), and serotonin transporter (SERT).^[116]^[118] When methamphetamine binds to TAAR1, it triggers transporter phosphorylation via protein kinase A (PKA) and protein kinase C (PKC) signaling, ultimately resulting in the internalization or reverse function of monoamine transporters.^[116]^[119] Methamphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a Ca2+/calmodulin-dependent protein kinase (CAMK)-dependent signaling pathway, in turn producing dopamine efflux.^[120]^[121]^[122] TAAR1 has been shown to reduce the firing rate of neurons through direct activation of G protein-coupled inwardly-rectifying potassium channels.^[123]^[124]^[125] TAAR1 activation by methamphetamine in astrocytes appears to negatively modulate the membrane expression and function of EAAT2, a type of glutamate transporter.^[57]

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

Methamphetamine is also an agonist of the alpha-2 adrenergic receptors and sigma receptors with a greater affinity for σ₁ than σ₂, and inhibits monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B).^[53]^[117]^[59] Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain.^[53]^[59] Dextromethamphetamine is a stronger psychostimulant, but levomethamphetamine has stronger peripheral effects, a longer half-life, and longer perceived effects among addicts.^[129]^[130]^[131] At high doses, both enantiomers of methamphetamine can induce similar stereotypy and methamphetamine psychosis,^[130] but levomethamphetamine has shorter psychodynamic effects.^[131]

Pharmacokinetics

The bioavailability of methamphetamine is 67% orally, 79% intranasally, 67 to 90% via inhalation (smoking), and 100% intravenously.^[3]^[4]^[5] Following oral administration, methamphetamine is well-absorbed into the bloodstream, with peak plasma methamphetamine concentrations achieved in approximately 3.13–6.3 hours post ingestion.^[132] Methamphetamine is also well absorbed following inhalation and following intranasal administration.^[4]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.^[4]^[132] The amphetamine metabolite peaks at 10–24 hours.^[4] Methamphetamine is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH.^[29]^[132] When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine.^[132] Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine.^[132]The elimination half-life of methamphetamine varies with a range of 5–30 hours, but it is on average 9 to 12 hours in most studies.^[4]^[3] The elimination half-life of methamphetamine does not vary by route of administration, but is subject to substantial interindividual variability.^[3]

CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase 3, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize methamphetamine or its metabolites in humans.^{[sources 2]} The primary metabolites are amphetamine and 4-hydroxymethamphetamine;^[132]other minor metabolites include: 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone, the metabolites of amphetamine.^[9]^[132]^[133] Among these metabolites, the active sympathomimetics are amphetamine, 4‑hydroxyamphetamine,^[139] 4‑hydroxynorephedrine,^[140] 4-hydroxymethamphetamine,^[132] and norephedrine.^[141] Methamphetamine is a CYP2D6 inhibitor.^[115]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.^[9]^[132]^[142] The known metabolic pathways include:

Metabolic pathways of methamphetamine in humans^{[sources 2]}

Methamphetamine

4-Hydroxymethamphetamine

4-Hydroxyphenylacetone

4-Hydroxynorephedrine

The primary metabolites of methamphetamine are amphetamine and 4-hydroxymethamphetamine.^[132] Human microbiota, particularly Lactobacillus, Enterococcus, and Clostridium species, contribute to the metabolism of methamphetamine via an enzyme which N-demethylates methamphetamine and 4-hydroxymethamphetamine into amphetamine and 4-hydroxyamphetamine respectively.^[143]^[144]

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.^[145]^[146]^[147]^[148] 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.^[149] 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.^[149]^[150]^[151] Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.^[152]

Chemistry

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.^[12] It is soluble in diethyl ether and ethanol as well as misciblewith chloroform.^[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 white crystalline powder.^[12] The hydrochloride salt is also freely soluble in ethanol and water.^[12] The crystal structure of either enantiomer is monoclinic with P2₁ space group; at 90 K (−183.2 °C; −297.7 °F), it has lattice parameters a = 7.10 Å, b = 7.29 Å, c = 10.81 Å, and β = 97.29°.^[153]

Degradation

A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration.^[154] A year-long study (also from 2011) showed that methamphetamine in soils is a persistent pollutant.^[155] In a 2013 study of bioreactors in wastewater, methamphetamine was found to be largely degraded within 30 days under exposure to light.^[156]

Synthesis

Racemic methamphetamine may be prepared starting from phenylacetone by either the Leuckart^[157] or reductive amination methods.^[158] 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.^[158] In this reaction, an iminium cation is formed as an intermediate which is reduced by the second equivalent of N-methylformamide.^[158] The intermediate formyl amide is then hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product.^[158] Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.^[158]

Methamphetamine synthesis

Method of methamphetamine synthesis of methamphetamine via reductive amination

Methods of methamphetamine synthesis via the Leuckart reaction

History, society, and culture

A methamphetamine tablet container — Pervitin, a methamphetamine brand used by German soldiers during World War II, was dispensed in these tablet containers.

Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine.^[161]^[162] Shortly after, methamphetamine was synthesized from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi.^[163] Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.^[164]

From 1938, methamphetamine was marketed on a large scale in Germany as a nonprescription drug under the brand name Pervitin, produced by the Berlin-based Temmler pharmaceutical company.^[165]^[166] It was used by all branches of the combined armed forces of the Third Reich, for its stimulant effects and to induce extended wakefulness.^[167]^[168] 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.^[169] 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.^[169] 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.^[170] Because of the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s.^[170]Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.^[162] For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act.^[171] Currently, methamphetamine is sold under the trade name Desoxyn, trademarked by the Danish pharmaceutical company Lundbeck.^[172] As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.^[173]

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.^[174]

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.^[175] 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.^[176] 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.^[177] 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.^[178] It was estimated over 18 tonnes of methamphetamine were produced under his watch.^[178]

Legal status

The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions.^[179]^[180] Methamphetamine has been placed in schedule II of the United Nations Convention on Psychotropic Substances treaty.^[180]

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.^[181]

Explanatory notes

^ Synonyms and alternate spellings include: N-methylamphetamine, desoxyephedrine, Syndrox, Methedrine, and Desoxyn.^[13]^[14]^[15] Common slang terms for methamphetamine include: meth, speed, crank and shabu (also sabu and shabu-shabu) in Indonesia and the Philippines,^[16]^[17]^[18]^[19] and for the hydrochloride crystal, crystal meth, glass, shards, and ice,^[20] and, in New Zealand, P.^[21]
^ 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.^[13]^[23]
^ Jump up to: ^a ^b ^c The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.^[24]^[25]
^ Transcription factors are proteins that increase or decrease the expression of specific genes.^[72]
^ 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.
^ 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 & linked receptors
  (Text color) Transcription factors

Reference notes

^ ^[4]^[29]^[37]^[47]^[100]^[101]^[102]
^ Jump up to: ^a ^b ^[8]^[9]^[10]^[11]^[132]^[133]^[134]^[135]^[136]^[137]^[138]

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σ Receptor agonists have been shown to facilitate dopamine release, through both σ-1 and σ-2 receptors [11–14].
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^ Jump up to: ^a ^b ^c ^d • Cisneros IE, Ghorpade A (October 2014). "Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes". Neuropharmacology. 85: 499–507. doi:10.1016/j.neuropharm.2014.06.011. PMC 4315503. PMID 24950453. TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance ... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function.
• Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMC 4532615. PMID 26092759. TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007)
^ Yuan J, Hatzidimitriou G, Suthar P, Mueller M, McCann U, Ricaurte G (March 2006). "Relationship between temperature, dopaminergic neurotoxicity, and plasma drug concentrations in methamphetamine-treated squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics. 316 (3): 1210–1218. doi:10.1124/jpet.105.096503. PMID 16293712. S2CID 11909155.
^ Jump up to: ^a ^b ^c ^d Rodvelt KR, Miller DK (September 2010). "Could sigma receptor ligands be a treatment for methamphetamine addiction?". Curr Drug Abuse Rev. 3 (3): 156–162. doi:10.2174/1874473711003030156. PMID 21054260.
^ 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.
^ Jump up to: ^a ^b ^c ^d Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.⁴¹. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.
^ 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.
^ Jump up to: ^a ^b ^c Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11(3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events
^ 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.
^ Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
^ Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717 (Figure 1). doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.
^ Jump up to: ^a ^b ^c Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12(11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression
^ Jump up to: ^a ^b ^c Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase
^ Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure
^ Hyman SE, Malenka RC, Nestler EJ (July 2006). "Neural mechanisms of addiction: the role of reward-related learning and memory" (PDF). Annu. Rev. Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. S2CID 15139406. Archived from the original (PDF) on 19 September 2018.
^ Jump up to: ^a ^b ^c ^d ^e ^f ^g ^h Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant-negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. 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 consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
^ 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.
^ Jump up to: ^a ^b ^c Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
^ Jump up to: ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).
^ Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Archived from the original on 13 October 2014. Retrieved 31 October 2014.
^ 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.
^ 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.
^ Jump up to: ^a ^b Blum 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.
^ Jump up to: ^a ^b Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity
^ 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.
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^ 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.
^ Jump up to: ^a ^b ^c Godino A, Jayanthi S, Cadet JL (2015). "Epigenetic landscape of amphetamine and methamphetamine addiction in rodents". Epigenetics. 10 (7): 574–80. doi:10.1080/15592294.2015.1055441. PMC 4622560. PMID 26023847.
^ 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.
^ 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.
^ 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.
^ Tokunaga I, Ishigami A, Kubo S, Gotohda T, Kitamura O (August 2008). "The peroxidative DNA damage and apoptosis in methamphetamine-treated rat brain". The Journal of Medical Investigation. 55 (3–4): 241–245. doi:10.2152/jmi.55.241. PMID 18797138.
^ Johnson Z, Venters J, Guarraci FA, Zewail-Foote M (June 2015). "Methamphetamine induces DNA damage in specific regions of the female rat brain". Clinical and Experimental Pharmacology & Physiology. 42 (6): 570–575. doi:10.1111/1440-1681.12404. PMID 25867833. S2CID 24182756.
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^ Jump up to: ^a ^b De 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.
^ 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.
^ Jump up to: ^a ^b ^c ^d Chan B, Freeman M, Kondo K, Ayers C, Montgomery J, Paynter R, Kansagara D (December 2019). "Pharmacotherapy for methamphetamine/amphetamine use disorder-a systematic review and meta-analysis". Addiction. 114 (12): 2122–2136. doi:10.1111/add.14755. PMID 31328345. S2CID 198136436.
^ 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.
^ O'Connor P. "Amphetamines: Drug Use and Abuse". Merck Manual Home Health Handbook. Merck. Archived from the original on 17 February 2007. Retrieved 26 September 2013.
^ Pérez-Mañá C, Castells X, Torrens M, Capellà D, Farre M (2013). Pérez-Mañá C (ed.). "Efficacy of psychostimulant drugs for amphetamine abuse or dependence". Cochrane Database Syst. Rev. 9 (9): CD009695. doi:10.1002/14651858.CD009695.pub2. PMID 23996457.
^ Jump up to: ^a ^b ^c ^d Shoptaw SJ, Kao U, Heinzerling K, Ling W (2009). Shoptaw SJ (ed.). "Treatment for amphetamine withdrawal". Cochrane Database Syst. Rev. 2009 (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMC 7138250. PMID 19370579. The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005)
^ Jump up to: ^a ^b ^c ^d Winslow BT, Voorhees KI, Pehl KA (2007). "Methamphetamine abuse". American Family Physician. 76 (8): 1169–1174. PMID 17990840.
^ Babies born to meth-affected mothers seem well behaved, but their passive nature masks a serious problem Archived 24 October 2021 at the Wayback Machine, Elicia Kennedy, ABC News Online, 3 January 2020
^ 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.
^ Albertson TE (2011). "Amphetamines". In Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AH (eds.). Poisoning & Drug Overdose (6th ed.). New York: McGraw-Hill Medical. pp. 77–79. ISBN 978-0-07-166833-0.
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^ Isbister GK, Buckley NA, Whyte IM (September 2007). "Serotonin toxicity: a practical approach to diagnosis and treatment" (PDF). Med. J. Aust. 187 (6): 361–365. doi:10.5694/j.1326-5377.2007.tb01282.x. PMID 17874986. S2CID 13108173. Archived (PDF) from the original on 4 July 2014. Retrieved 2 January 2014.
^ Malenka RC, Nestler EJ, Hyman SE (2009). "15". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 370. ISBN 978-0-07-148127-4. Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.
^ Jump up to: ^a ^b ^c Shoptaw SJ, Kao U, Ling W (2009). Shoptaw SJ, Ali R (eds.). "Treatment for amphetamine psychosis". Cochrane Database Syst. Rev. 2009 (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMC 7004251. PMID 19160215. A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ...
About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ...
Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.
^ Hofmann FG (1983). A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects (2nd ed.). New York: Oxford University Press. p. 329. ISBN 978-0-19-503057-0.
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^ Spencer MR, Miniño AM, Warner M (December 2022). "Drug Overdose Deaths in the United States, 2001-2021". NCHS Data Brief. National Center for Health Statistics (U.S.) (457): 1–8. doi:10.15620/cdc:122556. PMID 36598401. S2CID 254388862.
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^ Paone S, Clarkson L, Sin B, Punnapuzha S (August 2018). "Recognition of Sympathetic Crashing Acute Pulmonary Edema (SCAPE) and use of high-dose nitroglycerin infusion". The American Journal of Emergency Medicine. 36 (8): 1526.e5–1526.e7. doi:10.1016/j.ajem.2018.05.013. PMID 29776826. S2CID 21698404.
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^ Richards JR, Derlet RW, Duncan DR (September 1997). "Methamphetamine toxicity: treatment with a benzodiazepine versus a butyrophenone". Eur. J. Emerg. Med. 4 (3): 130–135. doi:10.1097/00063110-199709000-00003. PMID 9426992.
^ Richards JR, Derlet RW, Albertson TE. "Methamphetamine Toxicity: Treatment & Management". Medscape. WebMD. Archived from the original on 9 April 2016. Retrieved 20 April 2016.
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^ Jump up to: ^a ^b ^c Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J. Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
^ Jump up to: ^a ^b ^c "Methamphetamine: Targets". DrugBank. University of Alberta. 8 February 2013. Archived from the original on 28 December 2015. Retrieved 4 January 2014.
^ Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C (July 2001). "Trace amines: identification of a family of mammalian G protein-coupled receptors". Proc. Natl. Acad. Sci. U.S.A. 98 (16): 8966–8971. Bibcode:2001PNAS...98.8966B. doi:10.1073/pnas.151105198. PMC 55357. PMID 11459929.
^ Xie Z, Miller GM (July 2009). "A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain". J. Pharmacol. Exp. Ther. 330 (1): 316–325. doi:10.1124/jpet.109.153775. PMC 2700171. PMID 19364908.
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External links

[22] Synonyms and alternate spellings include: N-methylamphetamine, desoxyephedrine, Syndrox, Methedrine, and Desoxyn.^[13]^[14]^[15] Common slang terms for methamphetamine include: meth, speed, crank and shabu (also sabu and shabu-shabu) in Indonesia and the Philippines,^[16]^[17]^[18]^[19] and for the hydrochloride crystal, crystal meth, glass, shards, and ice,^[20] and, in New Zealand, P.^[21]

[25] 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.^[13]^[23]

[OTC_levmetamfetamine-28] Jump up to: ^a ^b ^c The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.^[24]^[25]

[77] Transcription factors are proteins that increase or decrease the expression of specific genes.^[72]

[78] 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.

[85] 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.

[66] 
Ion channel
G proteins & linked receptors
(Text color) Transcription factors

[110] [4]^[29]^[37]^[47]^[100]^[101]^[102]

[methamphetamine_metabolism-147] Jump up to: ^a ^b ^[8]^[9]^[10]^[11]^[132]^[133]^[134]^[135]^[136]^[137]^[138]

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[2] Anvisa (24 July 2023). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 25 July 2023). Archived from the original on 27 August 2023. Retrieved 27 August2023.

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[pmid25176528-5] Jump up to: ^a ^b ^c ^d Courtney KE, Ray LA (October 2014). "Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature". Drug Alcohol Depend. 143: 11–21. doi:10.1016/j.drugalcdep.2014.08.003. PMC 4164186. PMID 25176528.

[Bioavailability-6] Jump up to: ^a ^b ^c Rau T, Ziemniak J, Poulsen D (2015). "The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury". Prog. Neuropsychopharmacol. Biol. Psychiatry. 64: 231–6. doi:10.1016/j.pnpbp.2015.02.013. PMID 25724762. In humans, the oral bioavailability of methamphetamine is approximately 70% but increases to 100% following intravenous (IV) delivery (Ares-Santos et al., 2013).

[Pubchem1-7] "Methamphetamine: Toxicity". PubChem Compound. National Center for Biotechnology Information. Archived from the original on 4 January 2015. Retrieved 4 January 2015.

[Methamphetamine_–_p-hydroxymethamphetamine_CYP2D6_review-8] Jump up to: ^a ^b Sellers EM, Tyndale RF (2000). "Mimicking gene defects to treat drug dependence". Ann. N. Y. Acad. Sci. 909 (1): 233–246. Bibcode:2000NYASA.909..233S. doi:10.1111/j.1749-6632.2000.tb06685.x. PMID 10911933. S2CID 27787938. Methamphetamine, a central nervous system stimulant drug, is p-hydroxylated by CYP2D6 to less active p-OH-methamphetamine.

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[EMCDDA_profile-13] Jump up to: ^a ^b "Methamphetamine". Drug profiles. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). 8 January 2015. Archivedfrom the original on 15 April 2016. Retrieved 27 November 2018. The term metamfetamine (the International Non-Proprietary Name: INN) strictly relates to the specific enantiomer (S)-N,α-dimethylbenzeneethanamine.

[DB_ID-14] "Methamphetamine: Identification". DrugBank. University of Alberta. 8 February 2013. Archived from the original on 28 December 2015. Retrieved 1 January 2014.

[15] "Methedrine (methamphetamine hydrochloride): Uses, Symptoms, Signs and Addiction Treatment". Addictionlibrary.org. Archived from the original on 4 March 2016. Retrieved 16 January 2016.

[16] "Polisi Tangkap Bandar Shabu-shabu". Detik News (in Indonesian). Retrieved 29 July 2023.

[17] "P1-M shabu seized from 3 drug pushers". Manila Bulletin. Retrieved 29 July 2023.

[18] "Jadi pengedar sabu seorang IRT di Pidoli Dolok ditangkap Polisi - ANTARA News Sumatera Utara". ANTARA News Agency. Retrieved 29 July 2023.

[19] Marantal RD. "E-bike driver nabbed in drug bust, shabu worth almost P1 million seized". Philstar.com. Retrieved 29 July 2023.

[20] "Meth Slang Names". MethhelpOnline. Archived from the original on 7 December 2013. Retrieved 1 January 2014.

[21] "Methamphetamine and the law". Archived from the original on 28 January 2015. Retrieved 30 December 2014.

[Recent_advances_in_methamphetamine_neurotoxicity_–_2015_review-23] Yu S, Zhu L, Shen Q, Bai X, Di X (March 2015). "Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology". Behav. Neurol. 2015: 103969. doi:10.1155/2015/103969. PMC 4377385. PMID 25861156. In 1971, METH was restricted by US law, although oral METH (Ovation Pharmaceuticals) continues to be used today in the USA as a second-line treatment for a number of medical conditions, including attention deficit hyperactivity disorder (ADHD) and refractory obesity [3].

[24] "Levomethamphetamine". Pubchem Compound. National Center for Biotechnology Information. Archived from the original on 6 October 2014. Retrieved 27 November 2018.

[FDA_levmetamfetamine-26] "Code of Federal Regulations Title 21: Subchapter D – Drugs for human use, Part 341 – cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use". United States Food and Drug Administration. April 2015. Archived from the original on 25 December 2019. Retrieved 7 March 2016. Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in every 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.

[27] "Levomethamphetamine: Identification". Pubchem Compound. National Center for Biotechnology Information. Archived from the original on 6 October 2014. Retrieved 4 September 2017.

[AP-NBC_2004-29] "Meth's aphrodisiac effect adds to drug's allure". NBC News. Associated Press. 3 December 2004. Archived from the original on 12 August 2013. Retrieved 12 September 2019.

[Low_dose_Ntox-30] Jump up to: ^a ^b 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.

[pmid19328213-31] Jump up to: ^a ^b ^c ^d ^e ^f ^g ^h Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213. Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...
Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ...
There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ...
Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007).

[Desoxyn-32] Jump up to: ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x "Desoxyn Prescribing Information" (PDF). United States Food and Drug Administration. December 2013. Archived (PDF) from the original on 2 January 2014. Retrieved 6 January 2014.

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[pmid8341891-34] Mitler MM, Hajdukovic R, Erman MK (1993). "Treatment of narcolepsy with methamphetamine". Sleep. 16 (4): 306–317. PMC 2267865. PMID 8341891.

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[STD-47] Jump up to: ^a ^b Halkitis PN, Pandey Mukherjee P, Palamar JJ (2008). "Longitudinal Modeling of Methamphetamine Use and Sexual Risk Behaviors in Gay and Bisexual Men". AIDS and Behavior. 13 (4): 783–791. doi:10.1007/s10461-008-9432-y. PMC 4669892. PMID 18661225.

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[NeurClin-51] Rusinyak DE (2011). "Neurologic manifestations of chronic methamphetamine abuse". Neurologic Clinics. 29 (3): 641–655. doi:10.1016/j.ncl.2011.05.004. PMC 3148451. PMID 21803215.

[Darke-2008-52] Darke S, Kaye S, McKetin R, Duflou J (May 2008). "Major physical and psychological harms of methamphetamine use". Drug Alcohol Rev. 27 (3): 253–262. doi:10.1080/09595230801923702. PMID 18368606.

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[Glial_tox_review_–_Ntox_diagram-54] Jump up to: ^a ^b Beardsley PM, Hauser KF (2014). "Glial Modulators as Potential Treatments of Psychostimulant Abuse". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Advances in Pharmacology. Vol. 69. Academic Press. pp. 1–69. doi:10.1016/B978-0-12-420118-7.00001-9. ISBN 9780124201187. PMC 4103010. PMID 24484974. Glia (including astrocytes, microglia, and oligodendrocytes), which constitute the majority of cells in the brain, have many of the same receptors as neurons, secrete neurotransmitters and neurotrophic and neuroinflammatory factors, control clearance of neurotransmitters from synaptic clefts, and are intimately involved in synaptic plasticity. Despite their prevalence and spectrum of functions, appreciation of their potential general importance has been elusive since their identification in the mid-1800s, and only relatively recently have they been gaining their due respect. This development of appreciation has been nurtured by the growing awareness that drugs of abuse, including the psychostimulants, affect glial activity, and glial activity, in turn, has been found to modulate the effects of the psychostimulants

[Neuroimmune_meth_toxicity-55] Loftis JM, Janowsky A (2014). "Neuroimmune basis of methamphetamine toxicity". Neuroimmune Signaling in Drug Actions and Addictions. International Review of Neurobiology. Vol. 118. Academic Press. pp. 165–197. doi:10.1016/B978-0-12-801284-0.00007-5. ISBN 9780128012840. PMC 4418472. PMID 25175865. Collectively, these pathological processes contribute to neurotoxicity (e.g., increased BBB permeability, inflammation, neuronal degeneration, cell death) and neuropsychiatric impairments (e.g., cognitive deficits, mood disorders)
"Figure 7.1: Neuroimmune mechanisms of methamphetamine-induced CNS toxicity Archived 16 September 2018 at the Wayback Machine"

[Sigma-56] Jump up to: ^a ^b ^c ^d ^e Kaushal N, Matsumoto RR (March 2011). "Role of sigma receptors in methamphetamine-induced neurotoxicity". Curr Neuropharmacol. 9 (1): 54–57. doi:10.2174/157015911795016930. PMC 3137201. PMID 21886562. σ Receptors seem to play an important role in many of the effects of METH. They are present in the organs that mediate the actions of METH (e.g. brain, heart, lungs) [5]. In the brain, METH acts primarily on the dopaminergic system to cause acute locomotor stimulant, subchronic sensitized, and neurotoxic effects. σ Receptors are present on dopaminergic neurons and their activation stimulates dopamine synthesis and release [11–13]. σ-2 Receptors modulate DAT and the release of dopamine via protein kinase C (PKC) and Ca2+-calmodulin systems [14].
σ-1 Receptor antisense and antagonists have been shown to block the acute locomotor stimulant effects of METH [4]. Repeated administration or self administration of METH has been shown to upregulate σ-1 receptor protein and mRNA in various brain regions including the substantia nigra, frontal cortex, cerebellum, midbrain, and hippocampus [15, 16]. Additionally, σ receptor antagonists ... prevent the development of behavioral sensitization to METH [17, 18]. ...
σ Receptor agonists have been shown to facilitate dopamine release, through both σ-1 and σ-2 receptors [11–14].

[Neurotoxicity_2015-57] 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.

[pmid22392347-58] Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, Carvalho F, Bastos Mde L (August 2012). "Toxicity of amphetamines: an update". Arch. Toxicol. 86 (8): 1167–1231. doi:10.1007/s00204-012-0815-5. PMID 22392347. S2CID 2873101.

[Cruickshank-2009-59] Jump up to: ^a ^b Cruickshank CC, Dyer KR (July 2009). "A review of the clinical pharmacology of methamphetamine". Addiction. 104 (7): 1085–1099. doi:10.1111/j.1360-0443.2009.02564.x. PMID 19426289. S2CID 37079117.

[Cisneros_2014_and_review-60] Jump up to: ^a ^b ^c ^d • Cisneros IE, Ghorpade A (October 2014). "Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes". Neuropharmacology. 85: 499–507. doi:10.1016/j.neuropharm.2014.06.011. PMC 4315503. PMID 24950453. TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance ... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function.
• Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMC 4532615. PMID 26092759. TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007)

[61] Yuan J, Hatzidimitriou G, Suthar P, Mueller M, McCann U, Ricaurte G (March 2006). "Relationship between temperature, dopaminergic neurotoxicity, and plasma drug concentrations in methamphetamine-treated squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics. 316 (3): 1210–1218. doi:10.1124/jpet.105.096503. PMID 16293712. S2CID 11909155.

[SigmaB-62] Jump up to: ^a ^b ^c ^d Rodvelt KR, Miller DK (September 2010). "Could sigma receptor ligands be a treatment for methamphetamine addiction?". Curr Drug Abuse Rev. 3 (3): 156–162. doi:10.2174/1874473711003030156. PMID 21054260.

[Addiction_glossary-63] 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.

[Cellular_basis-64] Jump up to: ^a ^b ^c ^d Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.⁴¹. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict.

[Brain_disease-65] 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.

[Nestler-Renthal_Figure_2-67] Jump up to: ^a ^b ^c Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11(3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5.
Figure 2: Psychostimulant-induced signaling events

[Glutamate-dopamine_cotransmission_review-68] 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.

[Amphetamine_KEGG_ΔFosB-69] Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.

[Meth_cAMP/calcium-dependent_cascade-70] Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717 (Figure 1). doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695.

[Nestler1-71] Jump up to: ^a ^b ^c Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12(11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.
Figure 4: Epigenetic basis of drug regulation of gene expression

[Nestler2-72] Jump up to: ^a ^b ^c Nestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC 3569166. PMID 23430970. The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase

[c-Fos_repression-73] Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC 2607320. PMID 18640924. Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure

[Nestler,_Hyman,_and_Malenka_2-74] Hyman SE, Malenka RC, Nestler EJ (July 2006). "Neural mechanisms of addiction: the role of reward-related learning and memory" (PDF). Annu. Rev. Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. S2CID 15139406. Archived from the original (PDF) on 19 September 2018.

[Nestler-75] Jump up to: ^a ^b ^c ^d ^e ^f ^g ^h Robison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC 3272277. PMID 21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant-negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure^14,22–24. 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 consumption^14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.

[NHM-Transcription_factor-76] 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.

[What_the_ΔFosB?-79] Jump up to: ^a ^b ^c Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.

[Natural_and_drug_addictions-80] Jump up to: ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r Olsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).

[Alcoholism_ΔFosB-81] Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Archived from the original on 13 October 2014. Retrieved 31 October 2014.

[MPH_ΔFosB-82] 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.

[Nestler_2014_epigenetics-83] 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.

[ΔFosB_reward-84] Jump up to: ^a ^b Blum 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.

[Amph_and_sex_addiction-86] Jump up to: ^a ^b Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC 3865508. PMID 23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity

[pmid24685563-87] 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.

[pmid23313146-88] 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.

[pmid23643695-89] 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.

[Godino-90] Jump up to: ^a ^b ^c Godino A, Jayanthi S, Cadet JL (2015). "Epigenetic landscape of amphetamine and methamphetamine addiction in rodents". Epigenetics. 10 (7): 574–80. doi:10.1080/15592294.2015.1055441. PMC 4622560. PMID 26023847.

[pmid25446457-91] 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.

[pmid24239129-92] 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.

[pmid15120493-93] 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.

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Hi, where are you from?

Sunday, January 28, 2024

Attention Autistic: Merit To The American Board of Statistics?

Mark 4:8

You searched for

"PLANK" in the KJV Bible

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"CAMP" in the KJV Bible

Uses

Medical

Recreational

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Adverse effects

Physical

Meth mouth

Sexually transmitted infection

Psychological

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Epigenetic factors

Treatment and management

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Chemistry

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Name

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An Independent Mind, Knot Logic

An Independent Mind, Knot Logic

This Is Parameter

Karen A. Placek, aka Karen Placek, K.A.P., KAP

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