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Uses

Medical

In the United States, methamphetamine hydrochloride, sold under the brand name Desoxyn, is FDA-approved for the treatment of attention deficit hyperactivity disorder (ADHD);¹⁴¹⁵ however, the FDA notes that the limited therapeutic usefulness of methamphetamine should be weighed against the risks associated with its use.¹⁶ To avoid toxicity and risk of side effects, FDA guidelines recommend an initial dose of methamphetamine at doses 5–10 mg/day for ADHD in adults and children over six years of age, and may be increased at weekly intervals of 5 mg, up to 25 mg/day, until optimum clinical response is found; the usual effective dose is around 20–25 mg/day.¹⁷¹⁸¹⁹ Methamphetamine is sometimes prescribed off-label for obesity, narcolepsy, and idiopathic hypersomnia.²⁰²¹²² In the United States, methamphetamine's levorotary form is available in some over-the-counter (OTC) nasal decongestant products.²³²⁴

Although the pharmaceutical name "methamphetamine hydrochloride" may suggest a racemic mixture, Desoxyn contains enantiopure dextromethamphetamine, which is a more potent stimulant than both levomethamphetamine and racemic methamphetamine.²⁵²⁶ This naming convention deviates from the standard practice observed with other stimulants, such as Adderall and dextroamphetamine, where the dextrorotary enantiomer is explicitly identified as an active ingredient in both generic and brand-name pharmaceuticals.²⁷²⁸²⁹

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.³⁰ Methamphetamine hydrochloride dispensed in the United States is required to include a boxed warning regarding its potential for recreational misuse and addiction liability.³¹

Desoxyn and Desoxyn Gradumet are both pharmaceutical forms of the drug. The latter is no longer produced and is an extended-release form of the drug, flattening the curve of the effect of the drug while extending it.³²

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.³³

According to a National Geographic TV documentary on methamphetamine, an entire subculture known as party and play is based around sexual activity and methamphetamine use.³⁴ Participants in this subculture, which consists almost entirely of homosexual male methamphetamine users, will typically meet up through internet dating sites and have sex.³⁵ 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.³⁶ The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia (excessive daytime sleepiness).³⁷ The party and play subculture is prevalent in major US cities such as San Francisco and New York City.³⁸³⁹

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.⁴⁰ 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.⁴¹ 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.⁴² Owing to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.⁴³

Adverse effects

Physical

Cardiovascular

Methamphetamine is a sympathomimetic drug that causes vasoconstriction and tachycardia. Methamphetamine also promotes abnormal extra heart beats and irregular heart rhythms some of which may be life-threatening. ⁴⁴

Other physical effects

The effects can also include loss of appetite, hyperactivity, dilated pupils, flushed skin, excessive sweating, increased movement, dry mouth and teeth grinding (potentially leading to condition informally known as meth mouth), headache, rapid breathing, high body temperature, diarrhea, constipation, blurred vision, dizziness, twitching, numbness, tremors, dry skin, acne, and pale appearance.⁴⁵⁴⁶ Long-term meth users may have sores on their skin;⁴⁷⁴⁸ these may be caused by scratching due to itchiness or the belief that insects are crawling under their skin,⁴⁹ and the damage is compounded by poor diet and hygiene.⁵⁰ Numerous deaths related to methamphetamine overdoses have been reported.⁵¹⁵² Additionally, "[p]ostmortem examinations of human tissues have linked use of the drug to diseases associated with aging, such as coronary atherosclerosis and pulmonary fibrosis",⁵³ which may be caused "by a considerable rise in the formation of ceramides, pro-inflammatory molecules that can foster cell aging and death."⁵⁴

Dental and oral health ("meth mouth")

Main article: Meth mouth

Methamphetamine users, particularly heavy users, may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as meth mouth.⁵⁵ The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it.⁵⁶ 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)".⁵⁷⁵⁸ 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.⁵⁹

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.⁶⁰ 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.⁶¹ 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.⁶²⁶³ Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.⁶⁴⁶⁵

Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle.⁶⁶ The level of needle sharing among methamphetamine users is similar to that among other drug injection users.⁶⁷

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.⁶⁸⁶⁹⁷⁰ Peculiar to methamphetamine and related stimulants is "punding", persistent non-goal-directed repetitive activity.⁷¹ Methamphetamine use also has a high association with anxiety, depression, amphetamine psychosis, suicide, and violent behaviors.⁷²⁷³

Neurotoxicity

Methamphetamine is directly neurotoxic to dopaminergic neurons in both lab animals and humans.⁷⁴⁷⁵ Excitotoxicity, oxidative stress, metabolic compromise, UPS dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression and other processes contributed to this neurotoxicity.⁷⁶⁷⁷⁷⁸ In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of Parkinson's disease.⁷⁹ 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.⁸⁰ It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.⁸¹ Withdrawal of methamphetamine in dependent persons may lead to post-acute withdrawal which persists months beyond the typical withdrawal period.⁸²

Magnetic resonance imaging studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse neuroplastic changes in brain structure and function.⁸³ 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.⁸⁴ 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.⁸⁵

Methamphetamine has been shown to activate TAAR1 in human astrocytes and generate cAMP as a result.⁸⁶ 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.⁸⁷

Methamphetamine binds to and activates both sigma receptor subtypes, σ1 and σ2, with micromolar affinity.⁸⁸⁸⁹ 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.⁹⁰⁹¹

Addiction

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain, particularly the nucleus accumbens.⁹²⁹³ The most important transcription factors⁹⁴ that produce these alterations are ΔFosB, cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB).⁹⁵ 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 sufficient⁹⁶ for most of the behavioral and neural adaptations that arise from addiction.⁹⁷⁹⁸⁹⁹ Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.¹⁰⁰¹⁰¹ It has been implicated in addictions to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol, and substituted amphetamines, among others.^{102103104105106}

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).^107108109 Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug use (i.e., the alterations mediated by ΔFosB).¹¹⁰ ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.^111112113 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.¹¹⁴¹¹⁵ 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.^116117118 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.^119120121

Epigenetic factors

Methamphetamine addiction is persistent for many individuals, with 61% of individuals treated for addiction relapsing within one year.¹²² 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.¹²³

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.¹²⁴

A review in 2015¹²⁵ 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).¹²⁶ c-fos is well known to be important in addiction.¹²⁷ The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.¹²⁸

In methamphetamine addicted rats, epigenetic regulation through reduced acetylation of histones, in brain striatal neurons, caused reduced transcription of glutamate receptors.¹²⁹ Glutamate receptors play an important role in regulating the reinforcing effects of addictive drugs.¹³⁰

Administration of methamphetamine to rodents causes DNA damage in their brain, particularly in the nucleus accumbens region.¹³¹¹³² 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.¹³³ These alterations can be epigenetic scars in the chromatin that contribute to the persistent epigenetic changes found in methamphetamine addiction.

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).¹³⁴ 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.¹³⁵

As of December 2019, there is no effective pharmacotherapy for methamphetamine addiction.^136137138 A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in randomized controlled trials (RCTs) for amphetamine and methamphetamine addiction;¹³⁹ it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.¹⁴⁰ 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.¹⁴¹¹⁴²

Medication-Assisted Treatment (MAT) combines FDA-approved medications with behavioral therapies to address substance use disorders. This approach aims to reduce cravings and withdrawal symptoms, supporting individuals in their recovery process.¹⁴³

Dependence and withdrawal

Tolerance is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly.¹⁴⁴¹⁴⁵ In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.¹⁴⁶ Depression from methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.¹⁴⁷

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".¹⁴⁸ 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.¹⁴⁹ 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.¹⁵⁰

Methamphetamine that is present in a mother's bloodstream can pass through the placenta to a fetus and be secreted into breast milk.¹⁵¹ Infants born to methamphetamine-abusing mothers may experience a neonatal withdrawal syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and hypertonia.¹⁵² This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.¹⁵³

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.¹⁶⁷

A prospective cohort study of 330 children showed that at the age of 3, children with methamphetamine exposure showed increased emotional reactivity, as well as more signs of anxiety and depression; and at the age of 5, children showed higher rates of externalizing disorders and attention deficit hyperactivity disorder (ADHD).¹⁶⁸

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.¹⁶⁹¹⁷⁰ The cardiovascular effects are typically not noticed in young healthy people. Hypertension and tachycardia are not apparent unless measured. A moderate overdose of methamphetamine may induce symptoms such as: abnormal heart rhythm, confusion, difficult or painful urination, high or low blood pressure, high body temperature, over-active or over-responsive reflexes, muscle aches, severe agitation, rapid breathing, tremor, urinary hesitancy, and an inability to pass urine.¹⁷¹¹⁷² An extremely large overdose may produce symptoms such as adrenergic storm, methamphetamine psychosis, substantially reduced or no urine output, cardiogenic shock, bleeding in the brain, circulatory collapse, hyperpy rexia (i.e., dangerously high body temperature), pulmonary hypertension, kidney failure, rapid muscle breakdown, serotonin syndrome, and a form of stereotypy ("tweaking").¹⁷³ A methamphetamine overdose will likely also result in mild brain damage owing to dopaminergic and serotonergic neurotoxicity.¹⁷⁴¹⁷⁵ Death from methamphetamine poisoning is typically preceded by convulsions and coma.¹⁷⁶

Psychosis

Main section: Stimulant psychosis § Substituted amphetamines

Use of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g., paranoia, hallucinations, delirium, and delusions).¹⁷⁷¹⁷⁸ A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine use-induced psychosis states that about 5–15% of users fail to recover completely.¹⁷⁹¹⁸⁰ The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.¹⁸¹ Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.¹⁸²

Death from overdose

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 2021.¹⁸³ 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.¹⁸⁴ Unlike fentanyl which causes respiratory depression, methamphetamine is not a respiratory depressant. Some deaths are as a result of intracranial hemorrhage¹⁸⁵ and some deaths are cardiovascular in nature including flash pulmonary edema¹⁸⁶ and ventricular fibrillation.¹⁸⁷¹⁸⁸

Emergency treatment

Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of activated charcoal and sedation.¹⁸⁹ There is not enough evidence on hemodialysis or peritoneal dialysis in cases of methamphetamine intoxication to determine their usefulness.¹⁹⁰ 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.¹⁹¹ Hypertension presents a risk for intracranial hemorrhage (i.e., bleeding in the brain) and, if severe, is typically treated with intravenous phentolamine or nitroprusside.¹⁹² Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment.¹⁹³

Antipsychotics such as haloperidol are useful in treating agitation and psychosis from methamphetamine overdose.¹⁹⁴¹⁹⁵ Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity.¹⁹⁶¹⁹⁷ The mixed alpha- and beta-blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.¹⁹⁸ The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.¹⁹⁹

Interactions

Methamphetamine is metabolized by the liver enzyme CYP2D6, so CYP2D6 inhibitors will prolong the elimination half-life of methamphetamine.²⁰⁰²⁰¹ Methamphetamine also interacts with monoamine oxidase inhibitors (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.²⁰² Methamphetamine may decrease the effects of sedatives and depressants and increase the effects of antidepressants and other stimulants as well.²⁰³ Methamphetamine may counteract the effects of antihypertensives and antipsychotics owing to its effects on the cardiovascular system and cognition respectively.²⁰⁴ The pH of gastrointestinal content and urine affects the absorption and excretion of methamphetamine.²⁰⁵ Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite.²⁰⁶ Owing to the effect pH has on absorption, proton pump inhibitors, which reduce gastric acid, are known to interact with methamphetamine.²⁰⁷ Norepinephrine reuptake inhibitors (NRIs) like atomoxetine prevent norepinephrine release induced by amphetamines and have been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.^208209210 Similarly, norepinephrine–dopamine reuptake inhibitors (NRIs) like methylphenidate and bupropion prevent norepinephrine and dopamine release induced by amphetamines and bupropion has been found to reduce the subjective and sympathomimetic effects of methamphetamine in humans.^211212213214

Pharmacology

Pharmacodynamics

Methamphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor (GPCR) that regulates brain catecholamine systems.²²⁹²³⁰ 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).²³¹²³² 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.²³³²³⁴ 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.^235236237 TAAR1 has been shown to reduce the firing rate of neurons through direct activation of G protein-coupled inwardly-rectifying potassium channels.^238239240 TAAR1 activation by methamphetamine in astrocytes appears to negatively modulate the membrane expression and function of EAAT2, a type of glutamate transporter.²⁴¹

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.²⁴² 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.²⁴³ Other transporters that methamphetamine is known to inhibit are SLC22A3 and SLC22A5.²⁴⁴ SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.²⁴⁵²⁴⁶

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).^247248249 Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain.²⁵⁰²⁵¹ Dextromethamphetamine is a stronger psychostimulant, but levomethamphetamine has stronger peripheral effects, a longer half-life, and longer perceived effects among heavy substance users.^252253254 At high doses, both enantiomers of methamphetamine can induce similar stereotypy and methamphetamine psychosis,²⁵⁵ but levomethamphetamine has shorter psychodynamic effects.²⁵⁶

Pharmacokinetics

The bioavailability of methamphetamine is 67% orally, 79% intranasally, 67 to 90% via inhalation (smoking), and 100% intravenously.^257258259 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.²⁶⁰ Methamphetamine is also well absorbed following inhalation and following intranasal administration.²⁶¹ Because of the high lipophilicity of methamphetamine due to its methyl group, it can readily move through the blood–brain barrier faster than other stimulants, where it is more resistant to degradation by monoamine oxidase.^262263264 The amphetamine metabolite peaks at 10–24 hours.²⁶⁵ Methamphetamine is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH.²⁶⁶²⁶⁷ When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine.²⁶⁸ Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine.²⁶⁹ The elimination half-life of methamphetamine varies with a range of 5–30 hours, but it is on average 9 to 12 hours in most studies.²⁷⁰²⁷¹ The elimination half-life of methamphetamine does not vary by route of administration, but is subject to substantial interindividual variability.²⁷²

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.²⁷³ The primary metabolites are amphetamine and 4-hydroxymethamphetamine;²⁷⁴ other minor metabolites include: 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone, the metabolites of amphetamine.^275276277 Among these metabolites, the active sympathomimetics are amphetamine, 4‑hydroxyamphetamine,²⁷⁸ 4‑hydroxynorephedrine,²⁷⁹ 4-hydroxymethamphetamine,²⁸⁰ and norephedrine.²⁸¹ Methamphetamine is a CYP2D6 inhibitor.²⁸²

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.^283284285 The known metabolic pathways include:

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.^290291292293 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.²⁹⁴ Chiral separation is needed to assess the possible contribution of levomethamphetamine, which is an active ingredients in some OTC nasal decongestants,²⁹⁵ toward a positive test result.^296297298 Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.²⁹⁹

Chemistry

Methamphetamine is a chiral compound with two enantiomers, dextromethamphetamine and levomethamphetamine. At room temperature, the free base of methamphetamine is a clear and colorless liquid with an odor characteristic of geranium leaves.³⁰⁰ It is soluble in diethyl ether and ethanol as well as miscible with chloroform.³⁰¹

In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste.³⁰² 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.³⁰³ The hydrochloride salt is also freely soluble in ethanol and water.³⁰⁴ The crystal structure of either enantiomer is monoclinic with P21 space group; at 90 K (−183.2 °C; −297.7 °F), it has lattice parameters a = 7.10 Å, b = 7.29 Å, c = 10.81 Å, and β = 97.29°.³⁰⁵

Degradation

A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration.³⁰⁶ A year-long study (also from 2011) showed that methamphetamine in soils is a persistent pollutant.³⁰⁷ In a 2013 study of bioreactors in wastewater, methamphetamine was found to be largely degraded within 30 days under exposure to light.³⁰⁸

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 Leuckart³⁰⁹ or reductive amination methods.³¹⁰ 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.³¹¹ In this reaction, an iminium cation is formed as an intermediate which is reduced by the second equivalent of N-methylformamide.³¹² The intermediate formyl amide is then hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product.³¹³ Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.³¹⁴

History, society, and culture

Main article: History and culture of substituted amphetamines

Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine.³¹⁵³¹⁶ Shortly after, methamphetamine was synthesized from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi.³¹⁷ Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.³¹⁸

From 1938, methamphetamine was marketed on a large scale in Germany as a nonprescription drug under the brand name Pervitin, produced by the Berlin-based Temmler pharmaceutical company.³¹⁹³²⁰ It was used by all branches of the combined armed forces of the Third Reich, for its stimulant effects and to induce extended wakefulness.³²¹³²² Pervitin became colloquially known among the German troops as "Stuka-Tablets" (Stuka-Tabletten) and "Herman-Göring-Pills" (Hermann-Göring-Pillen), as a snide allusion to Göring's widely-known addiction to drugs. However, the side effects, particularly the withdrawal symptoms, were so serious that the army sharply cut back its usage in 1940.³²³ 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.³²⁴ 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.³²⁵ Because of the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s.³²⁶ Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.³²⁷ For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act.³²⁸ As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.³²⁹

Trafficking

The Golden Triangle (Southeast Asia), specifically Shan State, Myanmar, is the world's leading producer of methamphetamine as production has shifted to ya ba and crystalline methamphetamine, including for export to the United States and across East and Southeast Asia and the Pacific.³³⁰

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.³³¹ 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.³³² 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 2019.³³³ 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 2005.³³⁴ It was estimated over 18 tonnes of methamphetamine were produced under his watch.³³⁵

Legal status

Main article: Legal status of methamphetamine

The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions.³³⁶³³⁷ In some jurisdictions, it is legally available as a prescription medication. Methamphetamine has been placed in schedule II of the United Nations Convention on Psychotropic Substances treaty, indicating that it has limited medical use.³³⁸

Research

Animal models have shown that low-dose methamphetamine improves cognitive and behavioural functioning following TBI (traumatic brain injury).³³⁹ This is in contrast to high, repeated doses which cause neurotoxicity. These models demonstrate that low-dose methamphetamine increases neurogenesis and reduces apoptosis in the dentate gyrus of the hippocampus following TBI.³⁴⁰ It has also been found that TBI patients testing positive for methamphetamine at the time of emergency department admission have lower rates of mortality.³⁴¹

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.³⁴² Protection against methamphetamine-induced neurotoxicity has also been observed following administration of ascorbic acid (vitamin C),³⁴³ cobalamin (vitamin B12),³⁴⁴ and vitamin E.³⁴⁵

See also

• 18-MC
• Breaking Bad, a TV drama series centered on illicit methamphetamine synthesis
• Drug checking
• Faces of Meth, a drug prevention project
• Famprofazone, a non-steroidal anti-inflammatory drug yielding methamphetamine as a major metabolite
• 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

Footnotes

Reference notes

Further reading

• 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.
• Rusyniak DE (August 2011). "Neurologic manifestations of chronic methamphetamine abuse". Neurologic Clinics. 29 (3): 641–655. doi:10.1016/j.ncl.2011.05.004. PMC 3148451. PMID 21803215.
• Szalavitz M (21 November 2011). "Why the Myth of the Meth-Damaged Brain May Hinder Recovery". Time. Archived from the original on 22 September 2024. Retrieved 22 September 2024.

External links

• Methamphetamine Poison Information Monograph
• Drug Trafficking: Aryan Brotherhood Methamphetamine Operation Dismantled, FBI

References

1. Synonyms and alternate spellings include: N-methylamphetamine, desoxyephedrine, Syndrox, Methedrine, and Desoxyn.[15][16][17] Common slang terms for methamphetamine include: meth, speed, crank and shabu (also sabu and shabu-shabu) in Indonesia and the Philippines,[18][19][20][21] and for the hydrochloride crystal, crystal meth, glass, shards, and ice,[22] Tina,[23] and, in New Zealand, P.[24] ↩

2. Moszczynska A, Callan SP (September 2017). "Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment". The Journal of Pharmacology and Experimental Therapeutics. 362 (3): 474–488. doi:10.1124/jpet.116.238501. PMC 11047030. PMID 28630283. METH is a schedule II drug, which can only be prescribed for attention deficit hyperactivity disorder (ADHD), extreme obesity, or narcolepsy (as Desoxyn; Recordati Rare Diseases LLC, Lebanon, NJ), with amphetamine being prescribed more often for these conditions due to amphetamine having lower reinforcing potential than METH (Lile et al., 2013). ... As discussed earlier, the d-enantiomer has stronger CNS effects but is metabolized more quickly than the l-enantiomer, which is longer lasting due to the slower breakdown. ... l-METH, a vasoconstrictor, is the active constituent of the Vicks Inhaler decongestant (Proctor & Gamble, Cincinnati, OH), an over-the-counter product containing about 50 mg of the drug (Smith et al., 2014). Desoxyn, which is d-METH, is rarely medically prescribed due to its strong reinforcing properties. Therapeutic doses of Desoxyn are 20–25 mg daily, taken every 12 hours, with dosing not exceeding 60 mg/day https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11047030 ↩

3. Rau T, Ziemniak J, Poulsen D (January 2016). "The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury". Progress in Neuro-psychopharmacology & Biological Psychiatry. 64: 231–236. doi:10.1016/j.pnpbp.2015.02.013. ISSN 0278-5846. PMID 25724762. https://doi.org/10.1016%2Fj.pnpbp.2015.02.013 ↩

4. 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.[15][26] /wiki/International_Nonproprietary_Name ↩

5. Moszczynska A, Callan SP (September 2017). "Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment". The Journal of Pharmacology and Experimental Therapeutics. 362 (3): 474–488. doi:10.1124/jpet.116.238501. PMC 11047030. PMID 28630283. METH is a schedule II drug, which can only be prescribed for attention deficit hyperactivity disorder (ADHD), extreme obesity, or narcolepsy (as Desoxyn; Recordati Rare Diseases LLC, Lebanon, NJ), with amphetamine being prescribed more often for these conditions due to amphetamine having lower reinforcing potential than METH (Lile et al., 2013). ... As discussed earlier, the d-enantiomer has stronger CNS effects but is metabolized more quickly than the l-enantiomer, which is longer lasting due to the slower breakdown. ... l-METH, a vasoconstrictor, is the active constituent of the Vicks Inhaler decongestant (Proctor & Gamble, Cincinnati, OH), an over-the-counter product containing about 50 mg of the drug (Smith et al., 2014). Desoxyn, which is d-METH, is rarely medically prescribed due to its strong reinforcing properties. Therapeutic doses of Desoxyn are 20–25 mg daily, taken every 12 hours, with dosing not exceeding 60 mg/day https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11047030 ↩

6. Moszczynska A, Callan SP (September 2017). "Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment". The Journal of Pharmacology and Experimental Therapeutics. 362 (3): 474–488. doi:10.1124/jpet.116.238501. PMC 11047030. PMID 28630283. METH is a schedule II drug, which can only be prescribed for attention deficit hyperactivity disorder (ADHD), extreme obesity, or narcolepsy (as Desoxyn; Recordati Rare Diseases LLC, Lebanon, NJ), with amphetamine being prescribed more often for these conditions due to amphetamine having lower reinforcing potential than METH (Lile et al., 2013). ... As discussed earlier, the d-enantiomer has stronger CNS effects but is metabolized more quickly than the l-enantiomer, which is longer lasting due to the slower breakdown. ... l-METH, a vasoconstrictor, is the active constituent of the Vicks Inhaler decongestant (Proctor & Gamble, Cincinnati, OH), an over-the-counter product containing about 50 mg of the drug (Smith et al., 2014). Desoxyn, which is d-METH, is rarely medically prescribed due to its strong reinforcing properties. Therapeutic doses of Desoxyn are 20–25 mg daily, taken every 12 hours, with dosing not exceeding 60 mg/day https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11047030 ↩

7. The medication package insert for Desoxyn lists the chemical name (S)-N,α-dimethylbenzeneethanamine hydrochloride, which explicitly identifies the compound as dextromethamphetamine (the S-enantiomer) with no stereochemical ambiguity.[27] /wiki/Medication_package_insert ↩

8. Moszczynska A, Callan SP (September 2017). "Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment". The Journal of Pharmacology and Experimental Therapeutics. 362 (3): 474–488. doi:10.1124/jpet.116.238501. PMC 11047030. PMID 28630283. METH is a schedule II drug, which can only be prescribed for attention deficit hyperactivity disorder (ADHD), extreme obesity, or narcolepsy (as Desoxyn; Recordati Rare Diseases LLC, Lebanon, NJ), with amphetamine being prescribed more often for these conditions due to amphetamine having lower reinforcing potential than METH (Lile et al., 2013). ... As discussed earlier, the d-enantiomer has stronger CNS effects but is metabolized more quickly than the l-enantiomer, which is longer lasting due to the slower breakdown. ... l-METH, a vasoconstrictor, is the active constituent of the Vicks Inhaler decongestant (Proctor & Gamble, Cincinnati, OH), an over-the-counter product containing about 50 mg of the drug (Smith et al., 2014). Desoxyn, which is d-METH, is rarely medically prescribed due to its strong reinforcing properties. Therapeutic doses of Desoxyn are 20–25 mg daily, taken every 12 hours, with dosing not exceeding 60 mg/day https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11047030 ↩

9. The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[28][29] /wiki/International_Nonproprietary_Name ↩

10. "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. https://web.archive.org/web/20130812083225/http://www.nbcnews.com/id/6646180/ns/health-addictions/t/meths-aphrodisiac-effect-adds-drugs-allure/ ↩

11. Yu S, Zhu L, Shen Q, Bai X, Di X (March 2015). "Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology". Behavioural Neurology. 2015 (103969): 1–11. doi:10.1155/2015/103969. PMC 4377385. PMID 25861156. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377385 ↩

12. Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213. Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ... There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ... Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235 ↩

13. Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213. Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ... There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ... Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235 ↩

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15. 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. PMC 3260986. PMID 22089317. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260986 ↩

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17. Moszczynska A, Callan SP (September 2017). "Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment". The Journal of Pharmacology and Experimental Therapeutics. 362 (3): 474–488. doi:10.1124/jpet.116.238501. PMC 11047030. PMID 28630283. METH is a schedule II drug, which can only be prescribed for attention deficit hyperactivity disorder (ADHD), extreme obesity, or narcolepsy (as Desoxyn; Recordati Rare Diseases LLC, Lebanon, NJ), with amphetamine being prescribed more often for these conditions due to amphetamine having lower reinforcing potential than METH (Lile et al., 2013). ... As discussed earlier, the d-enantiomer has stronger CNS effects but is metabolized more quickly than the l-enantiomer, which is longer lasting due to the slower breakdown. ... l-METH, a vasoconstrictor, is the active constituent of the Vicks Inhaler decongestant (Proctor & Gamble, Cincinnati, OH), an over-the-counter product containing about 50 mg of the drug (Smith et al., 2014). Desoxyn, which is d-METH, is rarely medically prescribed due to its strong reinforcing properties. Therapeutic doses of Desoxyn are 20–25 mg daily, taken every 12 hours, with dosing not exceeding 60 mg/day https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11047030 ↩

18. Rau T, Ziemniak J, Poulsen D (January 2016). "The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury". Progress in Neuro-psychopharmacology & Biological Psychiatry. 64: 231–236. doi:10.1016/j.pnpbp.2015.02.013. ISSN 0278-5846. PMID 25724762. https://doi.org/10.1016%2Fj.pnpbp.2015.02.013 ↩

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20. Moszczynska A, Callan SP (September 2017). "Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment". The Journal of Pharmacology and Experimental Therapeutics. 362 (3): 474–488. doi:10.1124/jpet.116.238501. PMC 11047030. PMID 28630283. METH is a schedule II drug, which can only be prescribed for attention deficit hyperactivity disorder (ADHD), extreme obesity, or narcolepsy (as Desoxyn; Recordati Rare Diseases LLC, Lebanon, NJ), with amphetamine being prescribed more often for these conditions due to amphetamine having lower reinforcing potential than METH (Lile et al., 2013). ... As discussed earlier, the d-enantiomer has stronger CNS effects but is metabolized more quickly than the l-enantiomer, which is longer lasting due to the slower breakdown. ... l-METH, a vasoconstrictor, is the active constituent of the Vicks Inhaler decongestant (Proctor & Gamble, Cincinnati, OH), an over-the-counter product containing about 50 mg of the drug (Smith et al., 2014). Desoxyn, which is d-METH, is rarely medically prescribed due to its strong reinforcing properties. Therapeutic doses of Desoxyn are 20–25 mg daily, taken every 12 hours, with dosing not exceeding 60 mg/day https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11047030 ↩

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24. The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[28][29] /wiki/International_Nonproprietary_Name ↩

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26. The medication package insert for Desoxyn lists the chemical name (S)-N,α-dimethylbenzeneethanamine hydrochloride, which explicitly identifies the compound as dextromethamphetamine (the S-enantiomer) with no stereochemical ambiguity.[27] /wiki/Medication_package_insert ↩

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74. Yu S, Zhu L, Shen Q, Bai X, Di X (March 2015). "Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology". Behavioural Neurology. 2015 (103969): 1–11. doi:10.1155/2015/103969. PMC 4377385. PMID 25861156. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377385 ↩

75. Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213. Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ... There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ... Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235 ↩

76. Yu S, Zhu L, Shen Q, Bai X, Di X (March 2015). "Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology". Behavioural Neurology. 2015 (103969): 1–11. doi:10.1155/2015/103969. PMC 4377385. PMID 25861156. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377385 ↩

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78. Cruickshank CC, Dyer KR (July 2009). "A review of the clinical pharmacology of methamphetamine". Addiction. 104 (7): 1085–1099. doi:10.1111/j.1360-0443.2009.02564.x. PMID 19426289. S2CID 37079117. https://doi.org/10.1111%2Fj.1360-0443.2009.02564.x ↩

79. • Cisneros IE, Ghorpade A (October 2014). "Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes". Neuropharmacology. 85: 499–507. doi:10.1016/j.neuropharm.2014.06.011. PMC 4315503. PMID 24950453. TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance ... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. • Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMC 4532615. PMID 26092759. TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315503 ↩

80. Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213. Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ... There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ... Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235 ↩

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

82. Cruickshank CC, Dyer KR (July 2009). "A review of the clinical pharmacology of methamphetamine". Addiction. 104 (7): 1085–1099. doi:10.1111/j.1360-0443.2009.02564.x. PMID 19426289. S2CID 37079117. https://doi.org/10.1111%2Fj.1360-0443.2009.02564.x ↩

83. Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213. Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ... There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ... Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235 ↩

84. Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213. Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ... There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ... Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235 ↩

85. Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213. Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ... There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ... Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235 ↩

86. • Cisneros IE, Ghorpade A (October 2014). "Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes". Neuropharmacology. 85: 499–507. doi:10.1016/j.neuropharm.2014.06.011. PMC 4315503. PMID 24950453. TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance ... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. • Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMC 4532615. PMID 26092759. TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315503 ↩

87. • Cisneros IE, Ghorpade A (October 2014). "Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes". Neuropharmacology. 85: 499–507. doi:10.1016/j.neuropharm.2014.06.011. PMC 4315503. PMID 24950453. TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance ... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. • Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur. J. Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMC 4532615. PMID 26092759. TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315503 ↩

88. Kaushal N, Matsumoto RR (March 2011). "Role of sigma receptors in methamphetamine-induced neurotoxicity". Curr Neuropharmacol. 9 (1): 54–57. doi:10.2174/157015911795016930. PMC 3137201. PMID 21886562. σ Receptors seem to play an important role in many of the effects of METH. They are present in the organs that mediate the actions of METH (e.g. brain, heart, lungs) [5]. In the brain, METH acts primarily on the dopaminergic system to cause acute locomotor stimulant, subchronic sensitized, and neurotoxic effects. σ Receptors are present on dopaminergic neurons and their activation stimulates dopamine synthesis and release [11–13]. σ-2 Receptors modulate DAT and the release of dopamine via protein kinase C (PKC) and Ca2+-calmodulin systems [14].σ-1 Receptor antisense and antagonists have been shown to block the acute locomotor stimulant effects of METH [4]. Repeated administration or self administration of METH has been shown to upregulate σ-1 receptor protein and mRNA in various brain regions including the substantia nigra, frontal cortex, cerebellum, midbrain, and hippocampus [15, 16]. Additionally, σ receptor antagonists ... prevent the development of behavioral sensitization to METH [17, 18]. ... σ Receptor agonists have been shown to facilitate dopamine release, through both σ-1 and σ-2 receptors [11–14]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137201 ↩

89. Rodvelt KR, Miller DK (September 2010). "Could sigma receptor ligands be a treatment for methamphetamine addiction?". Curr Drug Abuse Rev. 3 (3): 156–162. doi:10.2174/1874473711003030156. PMID 21054260. /wiki/Doi_(identifier) ↩

90. Kaushal N, Matsumoto RR (March 2011). "Role of sigma receptors in methamphetamine-induced neurotoxicity". Curr Neuropharmacol. 9 (1): 54–57. doi:10.2174/157015911795016930. PMC 3137201. PMID 21886562. σ Receptors seem to play an important role in many of the effects of METH. They are present in the organs that mediate the actions of METH (e.g. brain, heart, lungs) [5]. In the brain, METH acts primarily on the dopaminergic system to cause acute locomotor stimulant, subchronic sensitized, and neurotoxic effects. σ Receptors are present on dopaminergic neurons and their activation stimulates dopamine synthesis and release [11–13]. σ-2 Receptors modulate DAT and the release of dopamine via protein kinase C (PKC) and Ca2+-calmodulin systems [14].σ-1 Receptor antisense and antagonists have been shown to block the acute locomotor stimulant effects of METH [4]. Repeated administration or self administration of METH has been shown to upregulate σ-1 receptor protein and mRNA in various brain regions including the substantia nigra, frontal cortex, cerebellum, midbrain, and hippocampus [15, 16]. Additionally, σ receptor antagonists ... prevent the development of behavioral sensitization to METH [17, 18]. ... σ Receptor agonists have been shown to facilitate dopamine release, through both σ-1 and σ-2 receptors [11–14]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137201 ↩

91. Rodvelt KR, Miller DK (September 2010). "Could sigma receptor ligands be a treatment for methamphetamine addiction?". Curr Drug Abuse Rev. 3 (3): 156–162. doi:10.2174/1874473711003030156. PMID 21054260. /wiki/Doi_(identifier) ↩

92. Hyman SE, Malenka RC, Nestler EJ (July 2006). "Neural mechanisms of addiction: the role of reward-related learning and memory" (PDF). Annu. Rev. Neurosci. 29: 565–598. doi:10.1146/annurev.neuro.29.051605.113009. PMID 16776597. S2CID 15139406. Archived from the original (PDF) on 19 September 2018. https://web.archive.org/web/20180919115435/https://pdfs.semanticscholar.org/fc1e/144037cd3c08aaf32d0a92b8c55a6ae451a5.pdf ↩

93. 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 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277 ↩

94. Transcription factors are proteins that increase or decrease the expression of specific genes.[78] /wiki/Gene_expression ↩

95. 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 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277 ↩

96. 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. ↩

97. Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681 ↩

98. 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 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277 ↩

99. Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. /wiki/Doi_(identifier) ↩

100. Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681 ↩

101. Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. /wiki/Doi_(identifier) ↩

102. 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 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277 ↩

103. Ruffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID 25083822. S2CID 19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. /wiki/Doi_(identifier) ↩

104. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

105. Kanehisa Laboratories (29 October 2014). "Alcoholism – Homo sapiens (human)". KEGG Pathway. Archived from the original on 13 October 2014. Retrieved 31 October 2014. http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354 ↩

106. Kim Y, Teylan MA, Baron M, Sands A, Nairn AC, Greengard P (February 2009). "Methylphenidate-induced dendritic spine formation and DeltaFosB expression in nucleus accumbens". Proc. Natl. Acad. Sci. U.S.A. 106 (8): 2915–2920. Bibcode:2009PNAS..106.2915K. doi:10.1073/pnas.0813179106. PMC 2650365. PMID 19202072. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650365 ↩

107. Nestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC 3898681. PMID 24459410. Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.41. ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681 ↩

108. 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 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277 ↩

109. 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384 ↩

110. 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 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277 ↩

111. 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 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277 ↩

112. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

113. Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, et al. (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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958 ↩

114. 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 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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277 ↩

115. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

116. 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. ↩

117. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

118. 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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508 ↩

119. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

120. Blum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, et al. (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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958 ↩

121. 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 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508 ↩

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149. Shoptaw SJ, Kao U, Heinzerling K, Ling W (2009). Shoptaw SJ (ed.). "Treatment for amphetamine withdrawal". Cochrane Database Syst. Rev. 2009 (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMC 7138250. PMID 19370579. The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138250 ↩

150. Shoptaw SJ, Kao U, Heinzerling K, Ling W (2009). Shoptaw SJ (ed.). "Treatment for amphetamine withdrawal". Cochrane Database Syst. Rev. 2009 (2): CD003021. doi:10.1002/14651858.CD003021.pub2. PMC 7138250. PMID 19370579. The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999) ... Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial "crash" that resolves within about a week (Gossop 1982;McGregor 2005) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138250 ↩

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154. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

155. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

156. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

157. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

158. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

159. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

160. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

161. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

162. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

163. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

164. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

165. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

166. 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). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704 ↩

167. Kennedy E (3 January 2020). "Babies born to meth-affected mothers seem well behaved, but their passive nature masks a serious problem". ABC News Online. Archived from the original on 24 October 2021. https://web.archive.org/web/20211024113948/https://www.abc.net.au/news/2020-01-03/the-hidden-problem-of-babies-born-to-meth-affected-mothers/11829668 ↩

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175. Krasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC 2731235. PMID 19328213. Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ... There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ... Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235 ↩

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