Methamphetamine
Clinical data | |||
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Pronunciation | /ˌmɛθæmˈfɛtəmiːn/ (METH-am-FET-ə-meen), /ˌmɛθəmˈfɛtəmiːn/ (METH-əm-FET-ə-meen), /ˌmɛθəmˈfɛtəmən/ (METH-əm-FET-ə-mən)[1] | ||
Trade names | Desoxyn, Methedrine | ||
Other names | N-methylamphetamine, N,α-dimethylphenethylamine, desoxyephedrine | ||
AHFS/Drugs.com | Monograph | ||
License data |
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ATC code | |||
Legal status | |||
Legal status |
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Protein binding | Varies widely[7] | ||
Metabolism | CYP2D6[8][9] and FMO3[10][11] | ||
Metabolites | • Amphetamine • Intravenous: <15 minutes[3] | ||
Elimination half-life | 9–12 hours (range 5–30 hours) (irrespective of route)[4][3] | ||
Duration of action | 8–12 hours[5] | ||
Excretion | Primarily kidney | ||
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Methamphetamine
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
In low to moderate doses, methamphetamine can
Methamphetamine belongs to the
Uses
Medical
In the United States, methamphetamine hydrochloride, under the trade name Desoxyn, has been approved by the FDA for treating
As methamphetamine is associated with a high potential for misuse, the drug is regulated under the
Desoxyn and Desoxyn Gradumet are both pharmaceutical forms of the drug. The latter is no longer produced and is a
Recreational
Methamphetamine is often used recreationally for its effects as a potent
According to a
Contraindications
Methamphetamine is
Adverse effects
Physical
The physical effects of methamphetamine can include
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
Neurotoxic and neuroimmunological
Methamphetamine is directly
Methamphetamine has been shown to activate
Methamphetamine binds to and activates both
Addictive
Addiction and dependence glossary[60][61][62] | |
---|---|
| |
Signaling cascade in the nucleus accumbens that results in psychostimulant addiction |
Current models of addiction from chronic drug use involve alterations in
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
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
As of December 2019[update], there is no effective
]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
Methamphetamine that is present in a mother's
Form of neuroplasticity or behavioral plasticity |
Type of reinforcer | Sources | |||||
---|---|---|---|---|---|---|---|
Opiates | Psychostimulants | High fat or sugar food | Sexual intercourse | Physical exercise (aerobic) |
Environmental enrichment | ||
MSNs
|
↑ | ↑ | ↑ | ↑ | ↑ | ↑ | [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 | |||||||
CREBphosphorylation in the nucleus accumbens |
↓ | ↓ | ↓ | ↓ | ↓ | [74] | |
Sensitized dopamine response in the nucleus accumbens |
No | Yes | No | Yes | [74] | ||
Altered striatal dopamine signaling | ↓ DRD3 |
↑ DRD3 |
↑ 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
Overdose
A methamphetamine overdose may result in a wide range of symptoms.
Psychosis
Use of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g.,
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
Antipsychotics such as
Interactions
Methamphetamine is metabolized by the liver enzyme
Pharmacology
Pharmacodynamics
Methamphetamine has been identified as a potent
In addition to its effect on the plasma membrane monoamine transporters, methamphetamine inhibits synaptic vesicle function by inhibiting
Methamphetamine is also an
Pharmacokinetics
The
The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[9][132][143] The known metabolic pathways include:
Metabolic pathways of methamphetamine in humans[sources 2]
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Detection in biological fluids
Methamphetamine and amphetamine are often measured in urine or blood as part of a drug test for sports, employment, poisoning diagnostics, and forensics.[146][147][148][149] Chiral techniques may be employed to help distinguish the source of the drug to determine whether it was obtained illicitly or legally via prescription or prodrug.[150] Chiral separation is needed to assess the possible contribution of levomethamphetamine, which is an active ingredients in some OTC nasal decongestants,[note 3] toward a positive test result.[150][151][152] Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.[153]
Chemistry
Methamphetamine is a
In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste.
Degradation
A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration.[155] A year-long study (also from 2011) showed that methamphetamine in soils is a persistent pollutant.[156] In a 2013 study of bioreactors in wastewater, methamphetamine was found to be largely degraded within 30 days under exposure to light.[157]
Synthesis
History, society, and culture
Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine.[162][163] Shortly after, methamphetamine was synthesized from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi.[164] Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.[165]
From 1938, methamphetamine was marketed on a large scale in Germany as a nonprescription drug under the brand name Pervitin, produced by the Berlin-based
A soldier going to battle on Pervitin usually found himself unable to perform effectively for the next day or two. Suffering from a drug hangover and looking more like a zombie than a great warrior, he had to recover from the side effects.
Some soldiers turned violent, committing war crimes against civilians; others attacked their own officers.[170] At the end of the war, it was used as part of a new drug: D-IX.
Obetrol, patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of obesity, was one of the first brands of pharmaceutical methamphetamine products.[171] Because of the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s.[171] Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.[163] For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act.[172] Currently, methamphetamine is sold under the trade name Desoxyn, trademarked by the Danish pharmaceutical company Lundbeck.[173] As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.[174]
Trafficking
The
Concerning the accelerating synthetic drug production in the region, the Cantonese Chinese syndicate Sam Gor, also known as The Company, is understood to be the main international crime syndicate responsible for this shift.[176] It is made up of members of five different triads. Sam Gor is primarily involved in drug trafficking, earning at least $8 billion per year.[177] Sam Gor is alleged to control 40% of the Asia-Pacific methamphetamine market, while also trafficking heroin and ketamine. The organization is active in a variety of countries, including Myanmar, Thailand, New Zealand, Australia, Japan, China, and Taiwan. Sam Gor previously produced meth in Southern China and is now believed to manufacture mainly in the Golden Triangle, specifically Shan State, Myanmar, responsible for much of the massive surge of crystal meth in circa 2019.[178] The group is understood to be headed by Tse Chi Lop, a gangster born in Guangzhou, China who also holds a Canadian passport.
Liu Zhaohua was another individual involved in the production and trafficking of methamphetamine until his arrest in 2005.[179] It was estimated over 18 tonnes of methamphetamine were produced under his watch.[179]
Legal status
The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions.[180][181] Methamphetamine has been placed in schedule II of the United Nations Convention on Psychotropic Substances treaty.[181]
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.[182]
See also
- 18-MC
- Breaking Bad, a TV drama series centered on illicit methamphetamine synthesis
- Drug checking
- Faces of Meth, a drug prevention project
- Harm reduction
- Methamphetamine and Native Americans
- Methamphetamine in Australia
- Methamphetamine in Bangladesh
- Methamphetamine in the Philippines
- Methamphetamine in the United States
- Montana Meth Project, a Montana-based organization aiming to reduce meth use among teenagers
- Recreational drug use
- Rolling meth lab, a transportable laboratory that is used to illegally produce methamphetamine
- Ya ba, Southeast Asian tablets containing a mixture of methamphetamine and caffeine
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]
- ^
- ^ 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
- G proteins & linked receptors(Text color) Transcription factors
Reference notes
References
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Methamphetamine, a central nervous system stimulant drug, is p-hydroxylated by CYP2D6 to less active p-OH-methamphetamine.
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The term metamfetamine (the International Non-Proprietary Name: INN) strictly relates to the specific enantiomer (S)-N,α-dimethylbenzeneethanamine.
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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].
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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.
- ^ "Levomethamphetamine: Identification". Pubchem Compound. National Center for Biotechnology Information. Archived from the original on 6 October 2014. Retrieved 4 September 2017.
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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). - ^ 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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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
- 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 - ^ 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]. - PMID 25861156.
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- ^ S2CID 37079117.
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TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007)
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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.
- 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. - ^ 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 - 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.
- PMID 24939695.
- ^ 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 - ^ 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
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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
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ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant-negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high-fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.
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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.
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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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The primary site of metabolism is in the liver by aromatic hydroxylation, N-dealkylation and deamination. At least seven metabolites have been identified in the urine, with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine. Other minor metabolites include 4-hydroxyamphetamine, norephedrine, and 4-hydroxynorephedrine. - S2CID 72333584.
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Further reading
- Szalavitz M. "Why the Myth of the Meth-Damaged Brain May Hinder Recovery". Time.com. Time USA, LLC.
- Hart CL, Marvin CB, Silver R, Smith EE (February 2012). "Is cognitive functioning impaired in methamphetamine users? A critical review". Neuropsychopharmacology. 37 (3): 586–608. PMID 22089317.
- Szalavitz M (21 November 2011). "Why the Myth of the Meth-Damaged Brain May Hinder Recovery". Time.