Methamphetamine

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Methamphetamine
INN: Metamfetamine
A racemic image of the methamphetamine compound
A 3d image of the levo-methamphetamine compound A 3d image of the dextro-methamphetamine compound
Clinical data
Pronunciation/ˌmɛθæmˈfɛtəmn/
(METH-am-FET-ə-meen), /ˌmɛθəmˈfɛtəmn/
(METH-əm-FET-ə-meen), /ˌmɛθəmˈfɛtəmən/
(METH-əm-FET-ə-mən)[1]
Trade namesDesoxyn, Methedrine
Other namesN-methylamphetamine, N,α-dimethylphenethylamine, desoxyephedrine
AHFS/Drugs.comMonograph
License data
ATC code
Legal status
Legal status
Intravenous: 100%[3][6]
Protein bindingVaries widely[7]
MetabolismCYP2D6[8][9] and FMO3[10][11]
MetabolitesAmphetamine
Intravenous: <15 minutes[3]
Elimination half-life9–12 hours (range 5–30 hours) (irrespective of route)[4][3]
Duration of action8–12 hours[5]
ExcretionPrimarily kidney
Identifiers
  • (RS)-N-methyl-1-phenylpropan-2-amine
mmHg[12]
  • CNC(C)Cc1ccccc1
  • InChI=1S/C10H15N/c1-9(11-2)8-10-6-4-3-5-7-10/h3-7,9,11H,8H2,1-2H3 checkY
  • Key:MYWUZJCMWCOHBA-UHFFFAOYSA-N checkY
  (verify)

Methamphetamine

Vyvanse
. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.

Both racemic methamphetamine and dextromethamphetamine are illicitly trafficked and sold owing to their potential for recreational use. The highest prevalence of illegal methamphetamine use occurs in parts of Asia and Oceania, and in the United States, where racemic methamphetamine and dextromethamphetamine are classified as

nasal decongestant in the United States.[note 3] Internationally, the production, distribution, sale, and possession of methamphetamine is restricted or banned in many countries, owing to its placement in schedule II of the United Nations Convention on Psychotropic Substances treaty. While dextromethamphetamine is a more potent drug, racemic methamphetamine is illicitly produced more often, owing to the relative ease of synthesis and regulatory limits of chemical precursor
availability.

In low to moderate doses, methamphetamine can

bleeding in the brain. Chronic high-dose use can precipitate unpredictable and rapid mood swings, stimulant psychosis (e.g., paranoia, hallucinations, delirium, and delusions) and violent behavior. Recreationally, methamphetamine's ability to increase energy has been reported to lift mood and increase sexual desire to such an extent that users are able to engage in sexual activity continuously for several days while binging the drug.[26] Methamphetamine is known to possess a high addiction liability (i.e., a high likelihood that long-term or high dose use will lead to compulsive drug use) and high dependence liability (i.e. a high likelihood that withdrawal symptoms will occur when methamphetamine use ceases). Withdrawal from methamphetamine after heavy use may lead to a post-acute-withdrawal syndrome, which can persist for months beyond the typical withdrawal period. Methamphetamine is neurotoxic to human midbrain dopaminergic neurons and, to a lesser extent, serotonergic neurons at high doses.[27][28] Methamphetamine neurotoxicity causes adverse changes in brain structure and function, such as reductions in grey matter volume in several brain regions, as well as adverse changes in markers of metabolic integrity.[28]

Methamphetamine belongs to the

positional isomer of these compounds, which share the common chemical formula C10H15N
.

Uses

Medical

Desoxyn (methamphetamine hydrochloride) 100 tablets

In the United States, methamphetamine hydrochloride, under the trade name Desoxyn, has been approved by the FDA for treating

nasal decongestant products.[note 3]

As methamphetamine is associated with a high potential for misuse, the drug is regulated under the

listed under Schedule II in the United States.[29] Methamphetamine hydrochloride dispensed in the United States is required to include a boxed warning regarding its potential for recreational misuse and addiction liability.[29]

Desoxyn and Desoxyn Gradumet are both pharmaceutical forms of the drug. The latter is no longer produced and is a

extended-release form of the drug, flattening the curve of the effect of the drug while extending it.[33]

Recreational

Methamphetamine is often used recreationally for its effects as a potent

euphoriant and stimulant as well as aphrodisiac qualities.[34]

According to a

internet dating sites and have sex.[34] Because of its strong stimulant and aphrodisiac effects and inhibitory effect on ejaculation, with repeated use, these sexual encounters will sometimes occur continuously for several days on end.[34] The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia (excessive daytime sleepiness).[34] The party and play subculture is prevalent in major US cities such as San Francisco and New York City.[34][35]

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

Contraindications

Methamphetamine is

seizures, thyroid problems, tics, or Tourette syndrome to monitor their symptoms while taking methamphetamine.[29] Owing to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.[29]

Adverse effects

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

Physical

The physical effects of methamphetamine can include

itchiness or the belief that insects are crawling under their skin,[38] and the damage is compounded by poor diet and hygiene.[39] Numerous deaths related to methamphetamine overdoses have been reported.[40][41]

Meth mouth

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.[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

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

Neurotoxic and neuroimmunological

Methamphetamine is directly

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

Methamphetamine has been shown to activate

EAAT2 (SLC1A2) levels and function in these cells.[57]

Methamphetamine binds to and activates both

apoptotic signaling cascades and the formation of reactive oxygen species.[53][59]

Addictive

Addiction and dependence glossary[60][61][62]
  • biopsychosocial
    disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
  • addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
  • dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
  • drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
  • drug withdrawal – symptoms that occur upon cessation of repeated drug use
  • physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens)
  • psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome)
  • 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 membrane
Plasma membrane
Cav1.2
DARPP-32
PP2B
CREB
ΔFosB
c-Fos
HDAC1
The image above contains clickable links
This diagram depicts the signaling events in the
nuclear factor kappa B), it induces an addictive state.[67][68]

Current models of addiction from chronic drug use involve alterations in

sex addictions, which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[note 6][74][79] These sex addictions (i.e., drug-induced compulsive sexual behaviors) are associated with a dopamine dysregulation syndrome which occurs in some patients taking dopaminergic drugs, such as amphetamine or methamphetamine.[74][78][79]

Epigenetic factors

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

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

A review in 2015

c-fos and the C-C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens (NAc).[83] c-fos is well known to be important in addiction.[84] The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.[83]

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

Administration of methamphetamine to rodents causes DNA damage in their brain, particularly in the nucleus accumbens region.[87][88] During repair of such DNA damages, persistent chromatin alterations may occur such as in the methylation of DNA or the acetylation or methylation of histones at the sites of repair.[89] These alterations can be epigenetic scars in the chromatin that contribute to the persistent epigenetic changes found in methamphetamine addiction.

Treatment and management

A 2018 systematic review and

psychodynamic therapy, and other combination therapies involving these.[90]

As of December 2019[update], there is no effective

prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.[92][verification needed
]

Dependence and withdrawal

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

According to the current Cochrane review on

Methamphetamine that is present in a mother's

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

Summary of addiction-related plasticity
Form of neuroplasticity
or behavioral plasticity
Type of reinforcer Sources
Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise
(aerobic)
Environmental
enrichment
MSNs
Tooltip medium spiny neurons
[74]
Behavioral plasticity
Escalation of intake Yes Yes Yes [74]
Psychostimulant
cross-sensitization
Yes Not applicable Yes Yes Attenuated Attenuated [74]
Psychostimulant
self-administration
[74]
Psychostimulant
conditioned place preference
[74]
Reinstatement of drug-seeking behavior
[74]
Neurochemical plasticity
CREBTooltip cAMP response element-binding protein phosphorylation

in the nucleus accumbens
[74]
Sensitized 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

externalizing and attention deficit/hyperactivity disorders.[99]

Overdose

A methamphetamine overdose may result in a wide range of symptoms.

hyperpy rexia (i.e., dangerously high body temperature), pulmonary hypertension, kidney failure, rapid muscle breakdown, serotonin syndrome, and a form of stereotypy ("tweaking").[sources 1] A methamphetamine overdose will likely also result in mild brain damage owing to dopaminergic and serotonergic neurotoxicity.[103][28] Death from methamphetamine poisoning is typically preceded by convulsions and coma.[29]

Psychosis

Use of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g.,

Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine use-induced psychosis states that about 5–15% of users fail to recover completely.[104][105] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[104] Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[106]

Death from overdose

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

Emergency treatment

Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of

nitroprusside.[4] Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment.[4]

Antipsychotics such as

beta-blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.[112] The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.[112]

Interactions

Methamphetamine is metabolized by the liver enzyme

proton pump inhibitors, which reduce gastric acid, are known to interact with methamphetamine.[29]

Pharmacology

An image of methamphetamine pharmacodynamics
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

EAAT2, a type of glutamate transporter.[57]

In addition to its effect on the plasma membrane monoamine transporters, methamphetamine inhibits synaptic vesicle function by inhibiting

presynaptic neuron, and their subsequent release into the synaptic cleft by the phosphorylated transporters.[127] Other transporters that methamphetamine is known to inhibit are SLC22A3 and SLC22A5.[126] SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.[117][128]

Methamphetamine is also an

methamphetamine psychosis,[130] but levomethamphetamine has shorter psychodynamic effects.[131]

Pharmacokinetics

The

sympathomimetics are amphetamine, 4‑hydroxyamphetamine,[140] 4‑hydroxynorephedrine,[141] 4-hydroxymethamphetamine,[132] and norephedrine.[142] Methamphetamine is a CYP2D6 inhibitor.[115]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[9][132][143] The known metabolic pathways include:

Metabolic pathways of methamphetamine in humans[sources 2]
The image above contains clickable links
The primary metabolites of methamphetamine are amphetamine and 4-hydroxymethamphetamine.
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.[144][145]

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

Shards of pure methamphetamine hydrochloride, also known as crystal meth

Methamphetamine is a

miscible with chloroform.[12]

In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste.

lattice parameters a = 7.10 Å, b = 7.29 Å, c = 10.81 Å, and β = 97.29°.[154]

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

hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product.[159] Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.[159]

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

History, society, and culture

A methamphetamine tablet container
Pervitin, a methamphetamine brand used by German soldiers during World War II, was dispensed in these tablet containers.
U.S. drug overdose related fatalities in 2017 were 70,200, including 10,333 of those related to psychostimulants (including methamphetamine).[160][161]

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

Stuka-Tablets" (Stuka-Tabletten) and "Herman-Göring-Pills" (Hermann-Göring-Pillen), as a snide allusion to Göring's widely-known addiction to drugs. However, the side effects, particularly the withdrawal symptoms, were so serious that the army sharply cut back its usage in 1940.[170]
By 1941, usage was restricted to a doctor's prescription, and the military tightly controlled its distribution. Soldiers would only receive a couple of tablets at a time, and were discouraged from using them in combat. Historian Łukasz Kamieński says,

A soldier going to battle on Pervitin usually found himself unable to perform effectively for the next day or two. Suffering from a drug hangover and looking more like a zombie than a great warrior, he had to recover from the side effects.

Some soldiers turned violent, committing war crimes against civilians; others attacked their own officers.[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

Yaba and crystalline methamphetamine, including for export to the United States and across East and Southeast Asia and the Pacific.[175]

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

Explanatory notes

  1. ^ 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]
  2. INN), respectively.[13][23]
  3. ^
    INN and USAN of levomethamphetamine.[24][25]
  4. ^ Transcription factors are proteins that increase or decrease the expression of specific genes.[72]
  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. G proteins & linked receptors
      (Text color) Transcription factors

Reference notes

References

  1. ^ "methamphetamine". Methamphetamine. Lexico. Archived from the original on 14 June 2021. Retrieved 22 April 2022.
  2. ^ Anvisa (24 July 2023). "RDC Nº 804 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 804 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 25 July 2023). Archived from the original on 27 August 2023. Retrieved 27 August 2023.
  3. ^
    S2CID 37079117
    .
  4. ^ .
  5. ^ .
  6. ^ . In humans, the oral bioavailability of methamphetamine is approximately 70% but increases to 100% following intravenous (IV) delivery (Ares-Santos et al., 2013).
  7. ^ "Methamphetamine: Toxicity". PubChem Compound. National Center for Biotechnology Information. Archived from the original on 4 January 2015. Retrieved 4 January 2015.
  8. ^
    S2CID 27787938
    . Methamphetamine, a central nervous system stimulant drug, is p-hydroxylated by CYP2D6 to less active p-OH-methamphetamine.
  9. ^ a b c d "Adderall XR Prescribing Information" (PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Archived (PDF) from the original on 30 December 2013. Retrieved 30 December 2013.
  10. ^
  11. ^ .
  12. ^ a b c d e f g "Methamphetamine: Chemical and Physical Properties". PubChem Compound. National Center for Biotechnology Information. Archived from the original on 4 January 2015. Retrieved 4 January 2015.
  13. ^ a b "Methamphetamine". Drug profiles. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). 8 January 2015. Archived from the original on 15 April 2016. Retrieved 27 November 2018. The term metamfetamine (the International Non-Proprietary Name: INN) strictly relates to the specific enantiomer (S)-N,α-dimethylbenzeneethanamine.
  14. ^ "Methamphetamine: Identification". DrugBank. University of Alberta. 8 February 2013. Archived from the original on 28 December 2015. Retrieved 1 January 2014.
  15. ^ "Methedrine (methamphetamine hydrochloride): Uses, Symptoms, Signs and Addiction Treatment". Addictionlibrary.org. Archived from the original on 4 March 2016. Retrieved 16 January 2016.
  16. ^ "Polisi Tangkap Bandar Shabu-shabu". Detik News (in Indonesian). Retrieved 29 July 2023.
  17. ^ "P1-M shabu seized from 3 drug pushers". Manila Bulletin. Retrieved 29 July 2023.
  18. ^ "Jadi pengedar sabu seorang IRT di Pidoli Dolok ditangkap Polisi - ANTARA News Sumatera Utara". ANTARA News Agency. Retrieved 29 July 2023.
  19. ^ Marantal RD. "E-bike driver nabbed in drug bust, shabu worth almost P1 million seized". Philstar.com. Retrieved 29 July 2023.
  20. ^ "Meth Slang Names". MethhelpOnline. Archived from the original on 7 December 2013. Retrieved 1 January 2014.
  21. ^ "Methamphetamine and the law". Archived from the original on 28 January 2015. Retrieved 30 December 2014.
  22. PMID 25861156
    . In 1971, METH was restricted by US law, although oral METH (Ovation Pharmaceuticals) continues to be used today in the USA as a second-line treatment for a number of medical conditions, including attention deficit hyperactivity disorder (ADHD) and refractory obesity [3].
  23. ^ "Levomethamphetamine". Pubchem Compound. National Center for Biotechnology Information. Archived from the original on 6 October 2014. Retrieved 27 November 2018.
  24. ^ "Code of Federal Regulations Title 21: Subchapter D – Drugs for human use, Part 341 – cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use". United States Food and Drug Administration. April 2015. Archived from the original on 25 December 2019. Retrieved 7 March 2016. Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in every 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.
  25. ^ "Levomethamphetamine: Identification". Pubchem Compound. National Center for Biotechnology Information. Archived from the original on 6 October 2014. Retrieved 4 September 2017.
  26. ^ "Meth's aphrodisiac effect adds to drug's allure". NBC News. Associated Press. 3 December 2004. Archived from the original on 12 August 2013. Retrieved 12 September 2019.
  27. ^
    PMID 25861156
    .
  28. ^ . 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).
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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
  52. 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)
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  53. ^ . 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].
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  57. ^ . 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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  60. .
  61. ^ . 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.
  62. . 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.
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    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
  64. . 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.
  65. ^ 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.
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    Figure 4: Epigenetic basis of drug regulation of gene expression
  68. ^ . 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
  69. . 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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  71. ^ . 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.
  72. .
  73. ^ . ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
  74. ^ . 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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  78. ^ . 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.
  79. ^ . 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.
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