Methamphetamine

Methamphetamine[note 1] (contracted from N-methylamphetamine) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity.[15] Methamphetamine was discovered in 1893 and exists as two enantiomers: levo-methamphetamine and dextro-methamphetamine.[note 2] Methamphetamine properly refers to a specific chemical, the racemic free base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms. It is rarely prescribed over concerns involving human neurotoxicity and potential for recreational use as an aphrodisiac and euphoriant, among other concerns, as well as the availability of safer substitute drugs with comparable treatment efficacy. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.

This article is about the stimulant drug. "Meth" and "crystal meth" redirect here. For other uses, see Meth (disambiguation).

Methamphetamine

Clinical data
Pronunciation	/ˌmɛθæmˈfɛtəmiːn/
Trade names	Desoxyn, Methedrine
Other names	N-methylamphetamine, N,α-dimethylphenethylamine, desoxyephedrine
AHFS/Drugs.com	Monograph
License data	US FDA: Methamphetamine
Pregnancy category	US: C (Risk not ruled out)
Dependence liability	Physical: None; Psychological: High
Addiction liability	High
Routes of administration	Medical: oral (ingestion) Recreational: oral, intravenous, intramuscular, subcutaneous, vapour inhalation, insufflation, rectal, vaginal
ATC code	N06BA03 (WHO)
Legal status
Legal status	AU: S8 (Controlled drug) 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: 70%[1] IV: 100%[1]
Protein binding	Varies widely[2]
Metabolism	CYP2D6[3][4] and FMO3[5][6]
Onset of action	Rapid[7]
Elimination half-life	5–30 hours[8]
Duration of action	10–20 hours[7]
Excretion	Primarily kidney
Identifiers
IUPAC name (RS)-N-methyl-1-phenylpropan-2-amine
CAS Number	537-46-2^Y (dl)-Methamphetamine hydrochloride: 300-42-5
PubChem CID	1206
IUPHAR/BPS	4803
DrugBank	DB01577^Y
ChemSpider	1169^Y
UNII	44RAL3456C (dl)-Methamphetamine hydrochloride: 24GNZ56D62^Y
KEGG	D08187^Y
ChEBI	CHEBI:6809^Y
ChEMBL	ChEMBL1201201^Y
PDB ligand	B40 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID8037128
ECHA 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) [9]
Boiling point	212 °C (414 °F) at 760 mmHg[9]
SMILES N(C(Cc1ccccc1)C)C
InChI InChI=1S/C10H15N/c1-9(11-2)8-10-6-4-3-5-7-10/h3-7,9,11H,8H2,1-2H3^Y Key:MYWUZJCMWCOHBA-UHFFFAOYSA-N^Y
(verify)

Both 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, 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, due 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 sometimes illicitly produced due to the relative ease of synthesis and limited availability of chemical precursors.

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.[19] 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 of methamphetamine after heavy use may lead to a post-acute-withdrawal syndrome, which can persist for months beyond the typical withdrawal period. Methamphetamine is neurotoxic to human midbrain dopaminergic neurons at high doses. Methamphetamine has been shown to have a higher affinity and, as a result, higher toxicity toward serotonergic neurons than amphetamine.[20][21] 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.[21]

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: C₁₀H₁₅N₁.

Uses

Medical

In the United States, dextromethamphetamine hydrochloride, under the trade name Desoxyn, has been approved by the FDA for treating ADHD and obesity in both adults and children;[22][23] however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use.[22] Methamphetamine is sometimes prescribed off label for narcolepsy and idiopathic hypersomnia.[24][25] In the United States, methamphetamine's levorotary form is available in some over-the-counter (OTC) nasal decongestant products.[note 3]

As methamphetamine is associated with a high potential for misuse, the drug is regulated under the Controlled Substances Act and is listed under Schedule II in the United States.[22] Methamphetamine hydrochloride dispensed in the United States is required to include a boxed warning regarding its potential for recreational misuse and addiction liability.[22]

Recreational

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

Methamphetamine is often used recreationally for its effects as a potent euphoriant and stimulant as well as aphrodisiac qualities.[26]

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.[26] Participants in this subculture, which consists almost entirely of homosexual male methamphetamine users, will typically meet up through internet dating sites and have sex.[26] Due to its strong stimulant and aphrodisiac effects and inhibitory effect on ejaculation, with repeated use, these sexual encounters will sometimes occur continuously for several days on end.[26] The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia (excessive daytime sleepiness).[26] The party and play subculture is prevalent in major US cities such as San Francisco and New York City.[26][27]

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.[22] 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.[22] 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.[22] Due to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.[22]

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 society.[28]

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.[22][29] Long-term meth users may have sores on their skin;[30][31][32] these may be caused by scratching due to itchiness[31] or the belief that insects are crawling under their skin,[30] and the damage is compounded by poor diet and hygiene.[32]

Meth mouth

Main article: Meth mouth

A suspected case of meth mouth

Methamphetamine users and addicts may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as meth mouth.[33] The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it.[33] 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)".[33][34] 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.[35]

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.[36] 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.[36] 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.[22][37] Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.[22][37]

Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle.[38] The level of needle sharing among methamphetamine users is similar to that among other drug injection users.[38]

Psychological

The psychological effects of methamphetamine can include euphoria, dysphoria, changes in libido, alertness, apprehension and concentration, decreased sense of fatigue, insomnia or wakefulness, self-confidence, sociability, irritability, restlessness, grandiosity and repetitive and obsessive behaviors.[22][29][39] Peculiar to methamphetamine and related stimulants is "punding", persistent non-goal-directed repetitive activity.[40] Methamphetamine use also has a high association with anxiety, depression, amphetamine psychosis, suicide, and violent behaviors.[41]

Neurotoxicity and neuroimmune response

This diagram depicts the neuroimmune mechanisms that mediate methamphetamine-induced neurodegeneration in the human brain.[42] The NF-κB-mediated neuroimmune response to methamphetamine use which results in the increased permeability of the blood–brain barrier arises through its binding at and activation of sigma receptors, the increased production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and damage-associated molecular pattern molecules (DAMPs), the dysregulation of glutamate transporters (specifically, EAAT1 and EAAT2) and glucose metabolism, and excessive Ca²⁺ ion influx in glial cells and dopamine neurons.[42][43][44]

Methamphetamine is directly neurotoxic to dopaminergic neurons in both lab animals and humans.[20][21] Excitotoxicity, oxidative stress, metabolic compromise, UPS dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression and other processes contributed to this neurotoxicity.[45][46][47] In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of Parkinson's disease.[48] In addition to its dopaminergic neurotoxicity, a review of evidence in humans indicated that high-dose methamphetamine abuse can also be neurotoxic to serotonergic neurons.[21] It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.[49] Withdrawal of methamphetamine in dependent pesons may lead to post-acute withdrawal which persists months beyond the typical withdrawal period.[47]

Magnetic resonance imaging studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse neuroplastic changes in brain structure and function.[21] In particular, methamphetamine appears to cause hyperintensity and hypertrophy of white matter, marked shrinkage of hippocampi, and reduced gray matter in the cingulate cortex, limbic cortex, and paralimbic cortex in recreational methamphetamine users.[21] Moreover, evidence suggests that adverse changes in the level of biomarkers of metabolic integrity and synthesis occur in recreational users, such as a reduction in N-acetylaspartate and creatine levels and elevated levels of choline and myoinositol.[21]

Methamphetamine has been shown to activate TAAR1 in human astrocytes and generate cAMP as a result.[48] 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.[48]

Methamphetamine binds to and activates both sigma receptor subtypes, σ₁ and σ₂, with micromolar affinity.[44][50] 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.[44][50]

Addiction

Addiction and dependence glossary[51][52][53][54]
addiction – a biopsychosocial disorder characterized by compulsively seeking to achieve a desired effect, such as intoxication, despite harm and adverse consequences to self and others addictive behavior – a behavior that is both rewarding and reinforcing addictive drug – a drug that is both rewarding and reinforcing dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake) drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose drug withdrawal – symptoms that occur upon cessation of repeated drug use physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens) psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia) reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach sensitization – an amplified response to a stimulus resulting from repeated exposure to it substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction Note: colored text contains article links. Nuclear pore Nuclear membrane Plasma membrane Cav1.2 NMDAR AMPAR DRD1 DRD5 DRD2 DRD3 DRD4 Gs Gi/o AC cAMP cAMP PKA CaM CaMKII DARPP-32 PP1 PP2B CREB 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,[55][56] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[55][57][58] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[55][59][60] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[61] 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.[59][60] 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.[59][60]

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.[62][63] 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).[63] 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.[52][63][65] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[52][65] It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.[63][65][66][67][68]

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).[52][63][69] Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug abuse (i.e., the alterations mediated by ΔFosB).[63] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[63][66][70] 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.[63][66] 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][66][71] 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.[66][70][71]

Epigenetic factors in methamphetamine addiction

Methamphetamine addiction is persistent for many individuals, with 61% of individuals treated for addiction relapsing within one year.[72] 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.[73]

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. Recently a crucial role has been found for epigenetic mechanisms in driving lasting changes in gene expression in the brain.[74]

A review in 2015[75] 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).[75] c-fos is well known to be important in addiction.[76] The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.[75]

In methamphetamine addicted rats, epigenetic regulation through reduced acetylation of histones, in brain striatal neurons, caused reduced transcription of glutamate receptors.[77] Glutamate receptors play an important role in regulating the reinforcing effects of drugs of abuse.[78]

Treatment and management

Further information: Addiction § Research

A 2018 systematic review and network meta-analysis of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that combination therapy with both contingency management and community reinforcement approach had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).[79] 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.[79]

As of December 2019, there is no effective pharmacotherapy for methamphetamine addiction.[80][81][82] A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in RCTs for amphetamine and methamphetamine addiction;[81] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.[81] 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.[81]

Dependence and withdrawal

Tolerance is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly.[83][84] In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.[85] Depression from methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.[86]

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".[85] 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.[85] 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.[85]

Methamphetamine that is present in a mother's bloodstream can pass through the placenta to a fetus and be secreted into breast milk.[86] Infants born to methamphetamine-abusing mothers may experience a neonatal withdrawal syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and hypertonia.[86] This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.[86]

Summary of addiction-related plasticity

Form of neuroplasticity or behavioral plasticity	Type of reinforcer						Sources
	Opiates	Psychostimulants	High fat or sugar food	Sexual intercourse	Physical exercise (aerobic)	Environmental enrichment
ΔFosB expression in nucleus accumbens D1-type MSNs	↑	↑	↑	↑	↑	↑	[66]
Behavioral plasticity
Escalation of intake	Yes	Yes	Yes				[66]
Psychostimulant cross-sensitization	Yes	Not applicable	Yes	Yes	Attenuated	Attenuated	[66]
Psychostimulant self-administration	↑	↑	↓		↓	↓	[66]
Psychostimulant conditioned place preference	↑	↑	↓	↑	↓	↑	[66]
Reinstatement of drug-seeking behavior	↑	↑			↓	↓	[66]
Neurochemical plasticity
CREB phosphorylation in the nucleus accumbens	↓	↓	↓		↓	↓	[66]
Sensitized dopamine response in the nucleus accumbens	No	Yes	No	Yes			[66]
Altered striatal dopamine signaling	↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3	↑DRD1, ↓DRD2, ↑DRD3		↑DRD2	↑DRD2	[66]
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	[66]
Changes in striatal opioid peptides	↑dynorphin No change: enkephalin	↑dynorphin	↓enkephalin		↑dynorphin	↑dynorphin	[66]
Mesocorticolimbic synaptic plasticity
Number of dendrites in the nucleus accumbens	↓	↑		↑			[66]
Dendritic spine density in the nucleus accumbens	↓	↑		↑			[66]

Methamphetamine babies

While newborn babies addicted to opioids show the jittery signs of immediate withdrawal, methamphetamine-affected babies show little more than a tendency to sleep.

Neonatologist Dr Ju Lee Oei of the University of New South Wales said not only were these babies often overlooked at birth, it was not until they approached school age that concerning behavioural and learning issues really started to emerge, by which time years of treatment opportunities had been missed. These children do not present with overt cerebral palsy or disability, but they have attention, behavioural and subtle cognitive losses that cannot be explained by anything else after accounting for lifestyle, environmental differences and genetic influences.[87] Unless the mother admits to taking methamphetamine, Dr Oei said it was difficult to identify babies as being at risk, and she predicted up to 90 per cent went undetected.

Researcher and nurse, Dr Stacey Blythe, said "Generally what would happen is the child presents as relatively healthy and they continue to grow and develop. But when they get behaviourally to four or five years old, their behaviours may look like those of a two- or three-year-old because the higher order areas of the brain haven't developed chronologically at the same rate." She said drug exposure could interfere with the child's working memory and their ability to control impulses and think flexibly.[87]

Overdose

A methamphetamine overdose may result in a wide range of symptoms.[8][22] A moderate overdose of methamphetamine may induce symptoms such as: abnormal heart rhythm, confusion, difficult and/or painful urination, high or low blood pressure, high body temperature, over-active and/or over-responsive reflexes, muscle aches, severe agitation, rapid breathing, tremor, urinary hesitancy, and an inability to pass urine.[8][29] An extremely large overdose may produce symptoms such as adrenergic storm, methamphetamine psychosis, substantially reduced or no urine output, cardiogenic shock, bleeding in the brain, circulatory collapse, hyperpyrexia (i.e., dangerously high body temperature), pulmonary hypertension, kidney failure, rapid muscle breakdown, serotonin syndrome, and a form of stereotypy ("tweaking").[sources 1] A methamphetamine overdose will likely also result in mild brain damage due to dopaminergic and serotonergic neurotoxicity.[91][21] Death from methamphetamine poisoning is typically preceded by convulsions and coma.[22]

Psychosis

Main section: Stimulant psychosis § Substituted amphetamines

Abuse of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g., paranoia, hallucinations, delirium, and delusions).[8][92] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely.[92][93] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[92] Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[94]

Emergency treatment

Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of activated charcoal and sedation.[8] There is not enough evidence on hemodialysis or peritoneal dialysis in cases of methamphetamine intoxication to determine their usefulness.[22] 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.[8] Hypertension presents a risk for intracranial hemorrhage (i.e., bleeding in the brain) and, if severe, is typically treated with intravenous phentolamine or nitroprusside.[8] Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment.[8]

Antipsychotics such as haloperidol are useful in treating agitation and psychosis from methamphetamine overdose.[95][96] Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity.[97] The mixed alpha- and beta-blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.[95] The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.[95]

Interactions

Methamphetamine is metabolized by the liver enzyme CYP2D6, so CYP2D6 inhibitors will prolong the elimination half-life of methamphetamine.[98] Methamphetamine also interacts with monoamine oxidase inhibitors (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.[22] Methamphetamine may decrease the effects of sedatives and depressants and increase the effects of antidepressants and other stimulants as well.[22] Methamphetamine may counteract the effects of antihypertensives and antipsychotics due to its effects on the cardiovascular system and cognition respectively.[22] The pH of gastrointestinal content and urine affects the absorption and excretion of methamphetamine.[22] Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite.[22] Due to the effect pH has on absorption, proton pump inhibitors, which reduce gastric acid, are known to interact with methamphetamine.[22]

Pharmacology

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

Pharmacodynamics

Methamphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor (GPCR) that regulates brain catecholamine systems.[99][100] 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).[99][101] 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.[99][102] 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.[103][104][105] TAAR1 has been shown to reduce the firing rate of neurons through direct activation of G protein-coupled inwardly-rectifying potassium channels.[106][107][108] TAAR1 activation by methamphetamine in astrocytes appears to negatively modulate the membrane expression and function of EAAT2, a type of glutamate transporter.[48]

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.[109] 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.[110] Other transporters that methamphetamine is known to inhibit are SLC22A3 and SLC22A5.[109] SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.[100][111]

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).[44][100][50] Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain.[44][50] Dextromethamphetamine is a stronger psychostimulant, but levomethamphetamine has stronger peripheral effects, a longer half-life, and longer perceived effects among addicts.[112][113][114] At high doses, both enantiomers of methamphetamine can induce similar stereotypy and methamphetamine psychosis,[113] but levomethamphetamine has shorter psychodynamic effects.[114]

Pharmacokinetics

Following oral administration, methamphetamine is well-absorbed into the bloodstream, with peak plasma methamphetamine concentrations achieved in approximately 3.13–6.3 hours post ingestion.[115] Methamphetamine is also well absorbed following inhalation and following intranasal administration.[8] Due to the high lipophilicity of methamphetamine, it can readily move through the blood–brain barrier faster than other stimulants, where it is more resistant to degradation by monoamine oxidase.[8][115] The amphetamine metabolite peaks at 10–24 hours.[8] Methamphetamine is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH.[22][115] When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine.[115] Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine.[115] The half-life of methamphetamine is variable with a range of 5–30 hours.[8]

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;[115] other minor metabolites include: 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone, the metabolites of amphetamine.[4][115][116] Among these metabolites, the active sympathomimetics are amphetamine, 4‑hydroxyamphetamine,[122] 4‑hydroxynorephedrine,[123] 4-hydroxymethamphetamine,[115] and norephedrine.[124] Methamphetamine is a CYP2D6 inhibitor.[98]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[4][115][125] The known metabolic pathways include:

Metabolic pathways of methamphetamine in humans[sources 2] Methamphetamine 4-Hydroxymethamphetamine 4-Hydroxyphenylacetone Phenylacetone Benzoic acid Hippuric acid Amphetamine Norephedrine 4-Hydroxyamphetamine 4-Hydroxynorephedrine The primary metabolites of methamphetamine are amphetamine and 4-hydroxymethamphetamine.[115] 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.[126][127]

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.[128][129][130][131] Chiral techniques may be employed to help distinguish the source the drug to determine whether it was obtained illicitly or legally via prescription or prodrug.[132] 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.[132][133][134] Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.[135]

Chemistry

Shards of pure methamphetamine hydrochloride, also known as crystal meth

Methamphetamine is a chiral compound with two enantiomers, dextromethamphetamine and levomethamphetamine. At room temperature, the free base of methamphetamine is a clear and colorless liquid with an odor characteristic of geranium leaves.[9] It is soluble in diethyl ether and ethanol as well as miscible with chloroform.[9] In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste.[9] 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.[9] The hydrochloride salt is also freely soluble in ethanol and water.[9]

Degradation

Bleach exposure time and concentration are correlated with destruction of methamphetamine.[136] Methamphetamine in soils has shown to be a persistent pollutant.[137] Methamphetamine is largely degraded within 30 days in a study of bioreactors under exposure to light in wastewater.[138]

Synthesis

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

Racemic methamphetamine may be prepared starting from phenylacetone by either the Leuckart[139] or reductive amination methods.[140] 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.[140] In this reaction, an iminium cation is formed as an intermediate which is reduced by the second equivalent of N-methylformamide.[140] The intermediate formyl amide is then hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product.[140] Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.[140]

Methamphetamine synthesis

Method of methamphetamine synthesis of methamphetamine via reductive amination

Methods of methamphetamine synthesis via the Leuckart reaction

History, society, and culture

Main article: History and culture of substituted amphetamines

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

U.S. drug overdose related fatalities in 2017 were 70,200, including 10,333 of those related to psychostimulants (including methamphetamine).[141][142]

Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine.[143][144] Shortly after, methamphetamine was synthesized from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi.[145] Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.[146]

During World War II, methamphetamine was sold in tablet form under the brand name Pervitin (not to be confused with Perviton, which is a synonym for Phenatine), produced by the Berlin-based Temmler pharmaceutical company. It was used by all branches of the combined Wehrmacht armed forces of the Third Reich, for its stimulant effects and to induce extended wakefulness.[147][148] Pervitin became colloquially known among the German troops as "Stuka-Tablets" (Stuka-Tabletten) and "Herman-Göring-Pills" (Hermann-Göring-Pillen). Side effects were so serious that the army sharply cut back its usage in 1940.[149] By 1941, usage was restricted to a doctor's prescription, and the military tightly controlled its distribution. Soldiers would only receive a couple tablets at a time, and were discouraged from using them in combat. Historian Lukasz Kamienski says "A soldier going to battle on Pervitin usually found himself unable to perform effectively for the next day or two. Suffering from a drug hangover and looking more like a zombie than a great warrior, he had to recover from the side effects." Some soldiers turned very violent, committing war crimes against civilians; others attacked their own officers.[149]

Obetrol, patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of obesity, was one of the first brands of pharmaceutical methamphetamine products.[150] Due to the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s.[150] Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.[144] For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act.[151] Currently, methamphetamine is sold under the trade name Desoxyn, trademarked by the Danish pharmaceutical company Lundbeck.[152] As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.[153]

Methamphetamine Trafficking

The Golden Triangle, specifically 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.[154] With respect to the accelerating synthetic drug production in the region, Sam Gor, also known as The Company, is understood to be the main international crime syndicate respsonsible for this shift.[155] It is made up of members of five different triads. Sam Gor is understood to be headed by Chinese-Canadian Tse Chi Lop. The Cantonese Chinese syndicate is primarily involved in drug trafficking, earning at least $8 billion per year.[156] 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 recent years.[157] The group is understood to be headed by Tse Chi Lop, a gangster born in Guangzhou, China.

In popular culture

The TV series Breaking Bad is centered on Walter White's production of methamphetamine.

Legal status

Main article: Legal status of methamphetamine

The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions.[158][159] Methamphetamine has been placed in schedule II of the United Nations Convention on Psychotropic Substances treaty.[159]

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.[160]

See also

• Breaking Bad, a TV series centered on illicit methamphetamine synthesis
• Faces of Meth, a drug prevention project
• Methamphetamine in Australia
• Methamphetamine in Bangladesh
• Methamphetamine in the Philippines
• Methamphetamine in the United States
• Montana Meth Project, a Montana-based organization aiming to reduce meth use among teenagers
• Rolling meth lab, a transportable laboratory that is used to illegally produce methamphetamine
• Ya ba, Southeast Asian tablets containing a mixture of methamphetamine and caffeine

Notes

1. Synonyms and alternate spellings include: N-methylamphetamine, desoxyephedrine, Syndrox, Methedrine, and Desoxyn.[10][11][12] Common slang terms for methamphetamine include: speed, meth, crystal, crystal meth, glass, shards, ice, and tic[13] and, in New Zealand, "P".[14]
2. Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.
   Levomethamphetamine and dextromethamphetamine are also known as L-methamphetamine, (R)-methamphetamine, or levmetamfetamine (International Nonproprietary Name [INN]) and D-methamphetamine, (S)-methamphetamine, or metamfetamine (INN), respectively.[10][16]
3. The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[17][18]
4. Transcription factors are proteins that increase or decrease the expression of specific genes.[64]
5. In simpler terms, this necessary and sufficient relationship means that ΔFosB overexpression in the nucleus accumbens and addiction-related behavioral and neural adaptations always occur together and never occur alone.
6. The associated research only involved amphetamine, not methamphetamine; however, this statement is included here due to the similarity between the pharmacodynamics and aphrodisiac effects of amphetamine and methamphetamine.

Image legend

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

Reference notes

1. [8][22][29][39][88][89][90]
2. [3][4][5][6][115][116][117][118][119][120][121]

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55. Renthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. PMC 2834246. PMID 19877494. [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. 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
56. 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.
57. 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.
58. Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Molecular Neurobiology. 51 (2): 696–717. doi:10.1007/s12035-014-8776-8. PMC 4359351. PMID 24939695. Figure 1
59. 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
60. 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
61. 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
62. 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.
63. 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.
64. 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.
65. 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. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
66. 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).
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69. 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.
70. 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.
71. 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
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Further reading

• Szalavitz, Maia. "Why the Myth of the Meth-Damaged Brain May Hinder Recovery". Time.com. Time USA, LLC.
• Hart CL, Marvin CB, Silver R, Smith EE (February 2012). "Is cognitive functioning impaired in methamphetamine users? A critical review". Neuropsychopharmacology. 37 (3): 586–608. doi:10.1038/npp.2011.276. ISSN 0893-133X. PMC 3260986. PMID 22089317. Lay summary – Time.com.

External links

• Methamphetamine Toxnet entry
• Methamphetamine Poison Information Monograph
• Drug Trafficking: Aryan Brotherhood Methamphetamine Operation Dismantled, FBI
• Neurologic manifestations of chronic methamphetamine abuse