# Methamphetamine

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Central nervous system stimulant

"Meth" redirects here. For other uses, see [Meth (disambiguation)](/source/Meth_(disambiguation)).

"Hiropon" and "Philopon" redirect here. For the Takashi Murakami sculpture, see [Hiropon (sculpture)](/source/Hiropon_(sculpture)).

Pharmaceutical compound

Methamphetamine INN: Metamfetamine Skeletal formula of methamphetamine Ball-and-stick models of methamphetamine enantiomers Clinical data Pronunciation /ˌmɛθæmˈfɛtəmiːn/ (METH-am-FET-ə-meen), /ˌmɛθəmˈfɛtəmiːn/ (METH-əm-FET-ə-meen), /ˌmɛθəmˈfɛtəmən/ (METH-əm-FET-ə-mən)[1] Trade names Desoxyn, others Other names N-methylamphetamine, N,α-dimethylphenethylamine, desoxyephedrine AHFS/Drugs.com Monograph Pregnancy category AU: X (High risk)The system is developed for medicine that can be prescribed, but the equivalent is category X. Dependence liability Physical: None Psychological: Very high Addiction liability Very high Routes of administration By mouth, intravenous, intramuscular, subcutaneous, inhalation, insufflation, rectal, vaginal Drug class Stimulant; Serotonin–norepinephrine–dopamine releasing agent ATC code N06BA03 (WHO) Legal status Legal status AU: S8 (Controlled drug) BR: Class F2 (Prohibited psychotropics)[2] CA: Schedule I DE: Anlage II (Authorized trade only, not prescriptible) NZ: Class A UK: Class A US: Schedule II[3] UN: Psychotropic Schedule II EU: Rx-only SE: Förteckning I Pharmacokinetic data Bioavailability Oral: 67%[4][5][6][7] Intranasal: 79%[4][5] Inhalation: 67–90%[4][5][6] Intravenous: 100%[4][7] Protein binding Varies widely[8] Metabolism CYP2D6[10][11] and FMO3[12][13] Metabolites • Amphetamine • Pholedrine • N-Hydroxymethamphetamine • Norephedrine[9] Onset of action Oral: 3 hours (peak)[4] Intranasal: <15 minutes[4] Inhalation: <18 minutes[4][5] Intravenous: <15 minutes[4] Elimination half-life 9–12 hours (range 5–30 hours); irrespective of route[5][4] Duration of action 8–12 hours[6] Excretion Primarily kidney Identifiers IUPAC name (RS)-N-methyl-1-phenylpropan-2-amine CAS Number 537-46-2 Y (dl)-Methamphetamine hydrochloride: 300-42-5 Y PubChem CID 1206 IUPHAR/BPS 4803 DrugBank DB01577 Y ChemSpider 1169 Y UNII 44RAL3456C (dl)-Methamphetamine hydrochloride: 24GNZ56D62 Y KEGG D08187 Y ChEBI CHEBI:6809 Y ChEMBL ChEMBL1201201 Y PDB ligand B40 (PDBe, RCSB PDB) CompTox Dashboard (EPA) DTXSID8037128 ECHA InfoCard 100.007.882 Chemical and physical data Formula C10H15N Molar mass 149.237 g·mol−1 3D model (JSmol) Interactive image Chirality Racemic mixture Melting point 170 °C (338 °F) [14] Boiling point 212 °C (414 °F) at 760 mmHg[14] SMILES CNC(C)Cc1ccccc1 InChI InChI=1S/C10H15N/c1-9(11-2)8-10-6-4-3-5-7-10/h3-7,9,11H,8H2,1-2H3 Y Key:MYWUZJCMWCOHBA-UHFFFAOYSA-N Y (verify)

**Methamphetamine**[note 1] is a [central nervous system](/source/Central_nervous_system) (CNS) [stimulant](/source/Stimulant) that is primarily used as a [recreational](/source/Recreational_drug_use) or [performance-enhancing](/source/Performance-enhancing_substance) drug and less commonly as a [second-line treatment](/source/Second-line_treatment) for [attention deficit hyperactivity disorder](/source/Attention_deficit_hyperactivity_disorder) (ADHD).[25] It has also been researched as a potential treatment for [traumatic brain injury](/source/Traumatic_brain_injury).[7] Methamphetamine was discovered in 1893 and exists as two [enantiomers](/source/Enantiomer): [levo-methamphetamine](/source/Levo-methamphetamine) and dextro-methamphetamine.[note 2] *Methamphetamine* properly refers to a specific chemical substance, the [racemic](/source/Racemic_mixture) [free base](/source/Free_base), which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms, but the [hydrochloride](/source/Hydrochloride) salt, commonly called crystal meth, is widely used. Methamphetamine is rarely prescribed over concerns involving its potential for misuse as an [aphrodisiac](/source/Aphrodisiac) and [euphoriant](/source/Euphoriant), among other concerns, as well as the availability of other drugs with comparable effects and treatment efficacy such as [dextroamphetamine](/source/Dextroamphetamine) and [lisdexamfetamine](/source/Lisdexamfetamine).[25] While pharmaceutical formulations of methamphetamine in the United States are labeled as methamphetamine hydrochloride, they contain dextromethamphetamine as the [active ingredient](/source/Active_ingredient).[25][note 3] Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.[25]

Both racemic methamphetamine and dextromethamphetamine are illicitly trafficked and sold owing to their potential for recreational use and ease of manufacture. The highest prevalence of illegal methamphetamine use occurs in parts of Asia and Oceania, and in the United States, where racemic methamphetamine and dextromethamphetamine are classified as [Schedule II](/source/List_of_Schedule_II_drugs_(US)) controlled substances. [Levomethamphetamine](/source/Levomethamphetamine) is available as an [over-the-counter](/source/Over-the-counter) (OTC) drug for use as an inhaled [nasal decongestant](/source/Nasal_decongestant) in the United States and is seldom abused.[28][note 4] Internationally, the production, distribution, sale, and possession of methamphetamine is restricted or banned in many countries, owing to its placement in schedule II of the [United Nations Convention on Psychotropic Substances](/source/Convention_on_Psychotropic_Substances) treaty. While dextromethamphetamine is a more potent drug, racemic methamphetamine is illicitly produced more often, owing to the relative ease of [synthesis](#Synthesis) and regulatory limits of [chemical precursor](/source/Precursor_(chemistry)) availability.

The effects of methamphetamine are nearly identical to other [substituted amphetamine](/source/Substituted_amphetamine).[31] In low to moderate and [therapeutic](/source/Therapeutic_index) doses (5–25 mg [orally](/source/Oral_administration)),[27] methamphetamine produces typical [SNDRA](/source/Serotonin%E2%80%93norepinephrine%E2%80%93dopamine_releasing_agent) effects and may [elevate mood](/source/Euphoria), increase alertness, concentration, and energy, [reduce appetite](/source/Anorexia_(symptom)), and [promote weight loss](/source/Anorectic). In [overdose](/source/Drug_overdose) or during extended [binges](/source/Substance_abuse), it may [induce psychosis](/source/Stimulant_psychosis#Substituted_amphetamines), [breakdown of skeletal muscle](/source/Rhabdomyolysis), [seizures](/source/Generalized_epilepsy), and [bleeding in the brain](/source/Cerebral_hemorrhage). Chronic high-dose use can precipitate unpredictable and rapid [mood swings](/source/Mood_swing), [stimulant psychosis](/source/Stimulant_psychosis) (e.g., [paranoia](/source/Paranoia), [hallucinations](/source/Hallucination), [delirium](/source/Delirium), and [delusions](/source/Delusion)), and [aggression](/source/Aggression). Recreationally, methamphetamine's ability to [increase energy](/source/Mental_energy) has been reported to lift mood and [increase sexual desire](/source/Aphrodisiac) to such an extent that users are able to engage in sexual activity continuously for several days while binging the drug.[32] Methamphetamine is known to possess a high [abuse](/source/Substance_abuse) liability (a high likelihood that extratherapeutic use will lead to [compulsive](/source/Compulsive_behavior) drug use) and high [psychological dependence](/source/Psychological_dependence) liability (a high likelihood that [withdrawal](/source/Drug_withdrawal) symptoms will occur when methamphetamine use ceases). Discontinuing methamphetamine after heavy use may lead to a [post-acute-withdrawal syndrome](/source/Post-acute-withdrawal_syndrome), which can persist for months beyond the typical withdrawal period. At high doses, like other [substituted amphetamines](/source/Substituted_amphetamine), methamphetamine is [neurotoxic](/source/Neurotoxicity) to human [midbrain](/source/Midbrain) [dopaminergic](/source/Dopaminergic_pathways) [neurons](/source/Neuron) and, to a lesser extent, [serotonergic](/source/Serotonin) neurons.[33][34][31] Methamphetamine neurotoxicity causes adverse changes in brain structure and function, such as reductions in [grey matter](/source/Grey_matter) volume in several brain regions, as well as adverse changes in markers of metabolic integrity.[34]

Methamphetamine belongs to the [substituted phenethylamine](/source/Substituted_phenethylamine) and [substituted amphetamine](/source/Substituted_amphetamine) [chemical classes](/source/Chemical_classification) and as a drug acts as a [serotonin–norepinephrine–dopamine releasing agent](/source/Serotonin%E2%80%93norepinephrine%E2%80%93dopamine_releasing_agent). It is related to the other [dimethylphenethylamines](/source/Dimethylphenethylamine) as a [positional isomer](/source/Positional_isomer) of these compounds, which share the common [chemical formula](/source/Chemical_formula) [C](/source/Carbon)10[H](/source/Hydrogen)15[N](/source/Nitrogen).

## Uses

### Medical

Bottle of 5mg Desoxyn (methamphetamine hydrochloride) tablets

In the United States, methamphetamine hydrochloride, sold under the brand name **Desoxyn**, is [FDA](/source/FDA)-approved for the treatment of attention deficit hyperactivity disorder (ADHD);[27][35] however, the FDA notes that the limited therapeutic usefulness of methamphetamine should be weighed against the risks associated with its use.[27] 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, which 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.[25][7][27] Methamphetamine is sometimes prescribed [off-label](/source/Off_label) for [obesity](/source/Obesity), [narcolepsy](/source/Narcolepsy), and [idiopathic hypersomnia](/source/Idiopathic_hypersomnia).[25][36][37] In the United States, [methamphetamine's levorotary form](/source/Levomethamphetamine) is available in some [over-the-counter](/source/Over-the-counter) (OTC) [nasal decongestant](/source/Nasal_decongestant) products.[25][note 4]

Although the pharmaceutical name "methamphetamine hydrochloride" may suggest a [racemic mixture](/source/Racemic_mixture), Desoxyn contains [enantiopure](/source/Enantiopure_drug) dextromethamphetamine, which is a more potent stimulant than both levomethamphetamine and racemic methamphetamine.[25][note 3] This naming convention deviates from the standard practice observed with other stimulants, such as [Adderall](/source/Adderall) and [dextroamphetamine](/source/Dextroamphetamine), where the dextrorotary [enantiomer](/source/Enantiomer) is explicitly identified as an [active ingredient](/source/Active_ingredient) in both [generic](/source/Generic_drug) and brand-name pharmaceuticals.[38][39][40]

As methamphetamine is associated with a high potential for misuse, the drug is regulated under the [Controlled Substances Act](/source/Controlled_Substances_Act) and is [listed under Schedule II](/source/List_of_Schedule_II_drugs_(US)) in the United States.[3] Methamphetamine hydrochloride dispensed in the United States is required to include a [boxed warning](/source/Boxed_warning) regarding its potential for recreational misuse and [addiction](/source/Addiction) liability.[27]

**Desoxyn Gradumet** was an [extended-release](/source/Extended-release) form of the drug. It is no longer produced.[41]

### Recreational

See also: [Party and play](/source/Party_and_play) and the [Recreational routes of methamphetamine administration](/source/History_and_culture_of_substituted_amphetamines#Recreational_routes_of_administration)

Methamphetamine is often used recreationally for its effects as a potent euphoriant and stimulant as well as [aphrodisiac](/source/Aphrodisiac) qualities.[42]

A subculture known as [party and play](/source/Party_and_play) is based around sexual activity and methamphetamine use.[42] Participants in this subculture, which consists mostly of homosexual male methamphetamine users, will typically meet up through [internet dating](/source/Internet_dating) sites and have sex.[42] Because of its strong stimulant and aphrodisiac effects and inhibitory effect on [ejaculation](/source/Ejaculation), with repeated use, these sexual encounters will sometimes occur continuously for several days on end.[42] The crash following the use of methamphetamine in this manner is very often severe, with marked [hypersomnia](/source/Hypersomnia) (excessive daytime sleepiness).[42] The party and play subculture is prevalent in major US cities such as San Francisco and New York City.[42][43]

Desoxyn tablets – pharmaceutical methamphetamine hydrochloride

Crystal meth – illicit methamphetamine hydrochloride

Methamphetamine shards on a metal milligram [scale](/source/Weighing_scale) tray

## Contraindications

Methamphetamine is [contraindicated](/source/Contraindicated) in individuals with a history of [substance use disorder](/source/Substance_use_disorder), [heart disease](/source/Heart_disease), or severe [agitation](/source/Irritability) or anxiety, or in individuals currently experiencing [arteriosclerosis](/source/Arteriosclerosis), [glaucoma](/source/Glaucoma), [hyperthyroidism](/source/Hyperthyroidism), or severe [hypertension](/source/Hypertension).[27] The FDA states that individuals who have experienced [hypersensitivity](/source/Hypersensitivity) reactions to other stimulants in the past or are currently taking [monoamine oxidase inhibitors](/source/Monoamine_oxidase_inhibitor) should not take methamphetamine.[27] The FDA also advises individuals with [bipolar disorder](/source/Bipolar_disorder), [depression](/source/Major_depressive_disorder), elevated [blood pressure](/source/Blood_pressure), liver or kidney problems, [mania](/source/Mania), [psychosis](/source/Psychosis), [Raynaud's phenomenon](/source/Raynaud's_phenomenon), [seizures](/source/Seizure), [thyroid](/source/Thyroid) problems, [tics](/source/Tic), or [Tourette syndrome](/source/Tourette_syndrome) to monitor their symptoms while taking methamphetamine.[27] Owing to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.[27]

## Adverse effects

A 2010 study ranking various illegal and legal drugs based on statements by drug-harm experts. Methamphetamine was found to be the fourth most damaging to users.[44] However, Nutt's concept and methodology were criticised sharply from a scientific perspective.[45][46]

Main short and long term adverse physical and mental effects that may appear in methamphetamine use

### Physical

#### Cardiovascular

Methamphetamine is a [sympathomimetic](/source/Sympathomimetic_drug) drug that causes [vasoconstriction](/source/Vasoconstriction) and [tachycardia](/source/Tachycardia). Methamphetamine also promotes [abnormal extra heartbeats](/source/Ectopic_beat) and [irregular heart rhythms](/source/Arrhythmia), which may be life-threatening. [47]

#### Other physical effects

The effects can also include [loss of appetite](/source/Anorexia_(symptom)), hyperactivity, [dilated pupils](/source/Dilated_pupils), [flushed skin](/source/Flushing_(physiology)), [excessive sweating](/source/Diaphoresis), [increased movement](/source/Psychomotor_agitation), dry mouth and [teeth grinding](/source/Bruxism) (potentially leading to condition informally known as *[meth mouth](/source/Meth_mouth)*), headache, [rapid breathing](/source/Tachypnea), [high body temperature](/source/Hyperthermia), diarrhea, constipation, [blurred vision](/source/Blurred_vision), [dizziness](/source/Dizziness), [twitching](/source/Fasciculation), [numbness](/source/Numbness), [tremors](/source/Tremor), dry skin, [acne](/source/Acne), and [pale appearance](/source/Pallor).[27][48] Long-term meth users may have [sores](/source/Ulcer_(dermatology)) on their skin;[49][50] these may be caused by scratching due to [itchiness](/source/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.[51] 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",[52] which may be caused "by a considerable rise in the formation of [ceramides](/source/Ceramide), pro-inflammatory molecules that can foster cell aging and death."[52]

#### Dental and oral health ("meth mouth")

Main article: [Meth mouth](/source/Meth_mouth)

A suspected case of [meth mouth](/source/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](/source/Meth_mouth).[53] The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it.[53] According to the [American Dental Association](/source/American_Dental_Association), meth mouth "is probably caused by a combination of drug-induced psychological and physiological changes resulting in [xerostomia](/source/Xerostomia) (dry mouth), extended periods of poor [oral hygiene](/source/Oral_hygiene), frequent consumption of high-calorie, carbonated beverages and bruxism (teeth grinding and clenching)".[53][54] As dry mouth is also a common side effect of other stimulants, which are not known to contribute severe tooth decay, many researchers suggest that methamphetamine-associated tooth decay is more due to users' other choices. They suggest the side effect has been exaggerated and stylized to create a stereotype of current users as a deterrence for new ones.[35]

#### Sexually transmitted infection

Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in both [HIV-positive](/source/HIV%2FAIDS) and unknown casual partners, an association more pronounced in HIV-positive participants.[55] 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.[55] Methamphetamine use allows users of both sexes to engage in prolonged sexual activity, which may cause genital sores and abrasions as well as [priapism](/source/Priapism) in men.[27][56] Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.[27][56]

Besides the sexual transmission of HIV, it may also be transmitted between users who [share a common needle](/source/Needle_sharing).[57] The level of needle sharing among methamphetamine users is similar to that among other drug injection users.[57]

### Psychological

The psychological effects of methamphetamine can include euphoria, dysphoria, changes in [libido](/source/Libido), [alertness](/source/Alertness), apprehension and [concentration](/source/Concentration), decreased sense of fatigue, [insomnia](/source/Insomnia) or [wakefulness](/source/Wakefulness), [self-confidence](/source/Self-confidence), sociability, irritability, restlessness, [grandiosity](/source/Grandiosity) and [repetitive and obsessive](/source/Fixation_(psychology)) behaviors.[27][48][58] Peculiar to methamphetamine and related stimulants is "[punding](/source/Punding)", persistent non-goal-directed repetitive activity.[59] Methamphetamine use also has a high association with [anxiety](/source/Anxiety), [depression](/source/Major_depressive_disorder), amphetamine psychosis, [suicide](/source/Suicide), and violent behaviors.[60][61]

### Neurotoxicity

This diagram depicts the [neuroimmune mechanisms](/source/Neuroimmune_system) that mediate methamphetamine-induced [neurodegeneration](/source/Neurodegeneration) in the human brain.[62] The [NF-κB](/source/NF-%CE%BAB)-mediated neuroimmune response to methamphetamine use which results in the increased permeability of the [blood–brain barrier](/source/Blood%E2%80%93brain_barrier) arises through its binding at and activation of [sigma receptors](/source/Sigma_receptor), the increased production of [reactive oxygen species](/source/Reactive_oxygen_species) (ROS), [reactive nitrogen species](/source/Reactive_nitrogen_species) (RNS), and [damage-associated molecular pattern molecules](/source/Damage-associated_molecular_pattern_molecules) (DAMPs), the dysregulation of [glutamate transporters](/source/Glutamate_transporter) (specifically, [EAAT1](/source/EAAT1) and [EAAT2](/source/EAAT2)) and [glucose metabolism](/source/Glucose_metabolism), and excessive [Ca2+ ion](/source/Calcium_in_biology) influx in [glial cells](/source/Glial_cell) and dopamine [neurons](/source/Neuron).[62][63][64]

Methamphetamine is [neurotoxic](/source/Neurotoxic) to dopaminergic systems in lab animals and is associated with dopaminergic toxicity in humans.[33][34] [Excitotoxicity](/source/Excitotoxicity), [oxidative stress](/source/Oxidative_stress), metabolic compromise, UPS dysfunction, protein nitration, [endoplasmic reticulum stress](/source/Endoplasmic_reticulum_stress_in_beta_cells), [p53 expression](/source/P53_expression) and other processes contributed to this neurotoxicity.[33][65][4] In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of [Parkinson's disease](/source/Parkinson's_disease).[66] In addition to its dopaminergic neurotoxicity, a review of human studies indicated that chronic methamphetamine use is associated with [serotonergic](/source/Serotonin) neurotoxicity.[34] It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.[67] Withdrawal of methamphetamine in dependent persons may lead to [post-acute withdrawal](/source/Post-acute-withdrawal_syndrome) which persists months beyond the typical withdrawal period.[4]

[Magnetic resonance imaging](/source/Magnetic_resonance_imaging) studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse [neuroplastic](/source/Neuroplastic) changes in brain structure and function.[34] In particular, methamphetamine appears to cause [hyperintensity](/source/Hyperintensity) and [hypertrophy](/source/Hypertrophy) of [white matter](/source/White_matter), marked shrinkage of [hippocampi](/source/Hippocampus), and reduced [gray matter](/source/Gray_matter) in the [cingulate cortex](/source/Cingulate_cortex), [limbic cortex](/source/Limbic_cortex), and [paralimbic cortex](/source/Paralimbic_cortex) in recreational methamphetamine users.[34] Moreover, evidence suggests that adverse changes in the level of [biomarkers](/source/Biomarker) of metabolic integrity and synthesis occur in recreational users, such as a reduction in [*N*-acetylaspartate](/source/N-acetylaspartate) and [creatine](/source/Creatine) levels and elevated levels of [choline](/source/Choline) and [myoinositol](/source/Myoinositol).[34]

Methamphetamine has been shown to activate [TAAR1](/source/TAAR1) in human [astrocytes](/source/Astrocyte) and generate [cAMP](/source/Cyclic_AMP) as a result.[66] Activation of astrocyte-localized TAAR1 appears to function as a mechanism by which methamphetamine attenuates membrane-bound [EAAT2](/source/EAAT2) (SLC1A2) levels and function in these cells.[66]

Methamphetamine binds to and activates both [sigma receptor](/source/Sigma_receptor) subtypes, [σ1](/source/Sigma-1_receptor) and [σ2](/source/Sigma-2_receptor), with micromolar affinity.[64][68] Sigma receptor activation may promote methamphetamine-induced neurotoxicity by facilitating [hyperthermia](/source/Hyperthermia), increasing dopamine synthesis and release, influencing microglial activation, and modulating [apoptotic](/source/Apoptotic) signaling cascades and the formation of reactive oxygen species.[64][68]

### Addiction

Addiction and dependence glossary[69][70][71] addiction – a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake) drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose drug withdrawal – symptoms that occur upon cessation of repeated drug use physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., delirium tremens and nausea) psychological dependence – dependence that is characterized by emotional-motivational withdrawal symptoms (e.g., anhedonia and anxiety) that affect cognitive functioning. reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach sensitization – an amplified response to a stimulus resulting from repeated exposure to it substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress drug tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose v t e

Signaling cascade in the nucleus accumbens that results in psychostimulant addiction v t e Note: colored text contains article links. Nuclear pore Nuclear membrane Plasma membrane Cav1.2 NMDAR AMPAR DRD1 DRD5 DRD2 DRD3 DRD4 Gs Gi/o AC cAMP cAMP PKA CaM CaMKII DARPP-32 PP1 PP2B CREB ΔFosB JunD c-Fos SIRT1 HDAC1 [Color legend 1] This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methamphetamine, and phenethylamine. Following presynaptic dopamine and glutamate co-release by such psychostimulants,[72][73] postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP-dependent pathway and a calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[72][74][75] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[72][76][77] c-Fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[78] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for 1–2 months, slowly accumulates following repeated high-dose exposure to stimulants through this process.[76][77] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[76][77]

Current models of addiction from chronic drug use involve alterations in [gene expression](/source/Gene_expression) in certain parts of the brain, particularly the [nucleus accumbens](/source/Nucleus_accumbens).[79][80] The most important [transcription factors](/source/Transcription_factor)[note 5] that produce these alterations are [ΔFosB](/source/%CE%94FosB), [cAMP](/source/Cyclic_adenosine_monophosphate) response element binding protein ([CREB](/source/CAMP_response_element_binding_protein)), and nuclear factor kappa B ([NFκB](/source/Nuclear_factor_kappa_B)).[80] ΔFosB plays a crucial role in the development of drug addictions, since its overexpression in [D1-type](/source/D1-type) [medium spiny neurons](/source/Medium_spiny_neuron) in the nucleus accumbens is [necessary and sufficient](/source/Necessary_and_sufficient#Definitions)[note 6] for most of the behavioral and neural adaptations that arise from addiction.[70][80][82] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that becomes increasingly more severe with further increases in ΔFosB expression.[70][82] It has been implicated in addictions to [alcohol](/source/Alcoholism), [cannabinoids](/source/Cannabinoid), [cocaine](/source/Cocaine), [methylphenidate](/source/Methylphenidate), [nicotine](/source/Nicotine), [opioids](/source/Opioid), [phencyclidine](/source/Phencyclidine), [propofol](/source/Propofol), and [substituted amphetamines](/source/Substituted_amphetamine), among others.[80][82][83][84][85]

[ΔJunD](/source/%CE%94JunD), a transcription factor, and [G9a](/source/EHMT2), a [histone methyltransferase](/source/Histone_methyltransferase) enzyme, both directly oppose the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its expression).[70][80][86] Sufficiently overexpressing ΔJunD in the nucleus accumbens with [viral vectors](/source/Viral_vector) can completely block many of the neural and behavioral alterations seen in chronic drug use (i.e., the alterations mediated by ΔFosB).[80] ΔFosB also plays an important role in regulating behavioral responses to [natural rewards](/source/Natural_reward), such as palatable food, sex, and exercise.[80][83][87] Since both natural rewards and addictive drugs [induce expression](/source/Inducible_gene) 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.[80][83] ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced [sex addictions](/source/Sex_addiction), which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use.[note 7][83][88] These sex addictions (i.e., drug-induced compulsive sexual behaviors) are associated with a [dopamine dysregulation syndrome](/source/Dopamine_dysregulation_syndrome) which occurs in some patients taking [dopaminergic drugs](/source/Dopaminergic#Supplements_and_drugs), such as amphetamine or methamphetamine.[83][87][88]

#### Epigenetic factors

Methamphetamine addiction is persistent for many individuals, with 61% of individuals treated for addiction relapsing within one year.[89] 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.[90]

The frequent persistence of addiction suggests that long-lasting changes in [gene expression](/source/Regulation_of_gene_expression#Regulation_of_transcription_in_addiction) 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](/source/Epigenetics) mechanisms in driving lasting changes in gene expression in the brain.[86]

A review in 2015[91] summarized a number of studies involving chronic methamphetamine use in rodents. Epigenetic alterations were observed in the brain [reward pathways](/source/Mesolimbic_pathway), including areas like [ventral tegmental area](/source/Ventral_tegmental_area), [nucleus accumbens](/source/Nucleus_accumbens), and dorsal [striatum](/source/Striatum), the [hippocampus](/source/Hippocampus), and the [prefrontal cortex](/source/Prefrontal_cortex). Chronic methamphetamine use caused gene-specific [histone acetylations, deacetylations](/source/Histone_acetylation_and_deacetylation) and [methylations](/source/Histone_methylation). Gene-specific DNA methylations in particular regions of the brain were also observed. The various epigenetic alterations caused [downregulations or upregulations](/source/Downregulation_and_upregulation) of specific genes important in addiction. For instance, chronic methamphetamine use caused [methylation of the lysine](/source/Histone_methylation#Function) in position 4 of histone 3 located at the [promoters](/source/Promoter_(genetics)) of the *[c-fos](/source/C-fos)* and the *[C-C chemokine receptor 2](/source/CCR2) (ccr2)* genes, activating those genes in the nucleus accumbens (NAc).[91] c-fos is well known to be important in [addiction](/source/Addiction).[92] The *ccr2* gene is also important in addiction, since mutational inactivation of this gene impairs addiction.[91]

In methamphetamine addicted rats, epigenetic regulation through reduced [acetylation](/source/Acetylation) of histones, in brain striatal neurons, caused reduced transcription of [glutamate receptors](/source/Glutamate_receptor#Conditions_with_demonstrated_associations_to_glutamate_receptors).[93] Glutamate receptors play an important role in regulating the reinforcing effects of addictive drugs.[94]

Administration of methamphetamine to rodents causes [DNA damage](/source/DNA_damage_(naturally_occurring)) in their brain, particularly in the [nucleus accumbens](/source/Nucleus_accumbens) region.[95][96] During repair of such DNA damages, persistent chromatin alterations may occur such as in the [methylation of DNA](/source/DNA_methylation) or the acetylation or [methylation of histones](/source/Histone_methylation) at the sites of repair.[97] These alterations can be [epigenetic scars](/source/Epigenetics) in the [chromatin](/source/Chromatin) that contribute to the persistent epigenetic changes found in methamphetamine addiction.

#### Treatment and management

Further information: [Addiction § Research](/source/Addiction#Research)

A 2018 systematic review and [network meta-analysis](/source/Network_meta-analysis) of 50 trials involving 12 different psychosocial interventions for amphetamine, methamphetamine, or cocaine addiction found that [combination therapy](/source/Combination_therapy) with both [contingency management](/source/Contingency_management) and [community reinforcement approach](/source/Community_reinforcement_approach) had the highest efficacy (i.e., abstinence rate) and acceptability (i.e., lowest dropout rate).[98] Other treatment modalities examined in the analysis included [monotherapy](/source/Monotherapy) with contingency management or community reinforcement approach, [cognitive behavioral therapy](/source/Cognitive_behavioral_therapy), [12-step programs](/source/12-step_program), non-contingent reward-based therapies, [psychodynamic therapy](/source/Psychodynamic_therapy), and other combination therapies involving these.[98]

As of December 2019[\[update\]](https://en.wikipedia.org/w/index.php?title=Methamphetamine&action=edit), there is no effective [pharmacotherapy](/source/Pharmacotherapy) for methamphetamine addiction.[99][100][101] A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in [randomized controlled trials](/source/Randomized_controlled_trial) (RCTs) for amphetamine and methamphetamine addiction;[100] it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration.[100] There was low-to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, [mirtazapine](/source/Mirtazapine), [sertraline](/source/Sertraline)), antipsychotics ([aripiprazole](/source/Aripiprazole)), anticonvulsants ([topiramate](/source/Topiramate), [baclofen](/source/Baclofen), [gabapentin](/source/Gabapentin)), [naltrexone](/source/Naltrexone), [varenicline](/source/Varenicline), [citicoline](/source/Citicoline), [ondansetron](/source/Ondansetron), [prometa](/source/Prometa), [riluzole](/source/Riluzole), [atomoxetine](/source/Atomoxetine), dextroamphetamine, and [modafinil](/source/Modafinil).[100][102]

[Medication-Assisted Treatment](/source/Opioid_agonist_therapy) (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.[103]

#### Dependence and withdrawal

[Tolerance](/source/Drug_tolerance) is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly.[104][105] In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.[106] [Depression](/source/Depression_(mood)) from methamphetamine withdrawal lasts longer and is more severe than that of [cocaine](/source/Cocaine) withdrawal.[107]

According to the current Cochrane review on [drug dependence](/source/Drug_dependence) and [withdrawal](/source/Drug_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".[106] 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.[106] Methamphetamine withdrawal symptoms can include anxiety, [drug craving](/source/Craving_(withdrawal)), dysphoric mood, [fatigue](/source/Fatigue_(medical)), [increased appetite](/source/Hyperphagia), [increased movement](/source/Psychomotor_agitation) or [decreased movement](/source/Psychomotor_retardation), [lack of motivation](/source/Anhedonia), [sleeplessness](/source/Insomnia) or [sleepiness](/source/Hypersomnia), and [vivid or lucid dreams](/source/Lucid_dream).[106]

Methamphetamine that is present in a mother's [bloodstream](/source/Bloodstream) can pass through the [placenta](/source/Placenta) to a [fetus](/source/Fetus) and be secreted into [breast milk](/source/Breast_milk).[107] Infants born to methamphetamine-abusing mothers may experience a [neonatal withdrawal](/source/Neonatal_withdrawal) syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and [hypertonia](/source/Hypertonia).[107] This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.[107]

Summary of addiction-related plasticity Form of neuroplasticity or behavioral plasticity Type of reinforcer Ref. Opiates Psychostimulants High fat or sugar food Sexual intercourse Physical exercise (aerobic) Environmental enrichment ΔFosB expression in nucleus accumbens D1-type MSNsTooltip medium spiny neurons ↑ ↑ ↑ ↑ ↑ ↑ [83] Behavioral plasticity Escalation of intake Yes Yes Yes [83] Psychostimulant cross-sensitization Yes Not applicable Yes Yes Attenuated Attenuated [83] Psychostimulant self-administration ↑ ↑ ↓ ↓ ↓ [83] Psychostimulant conditioned place preference ↑ ↑ ↓ ↑ ↓ ↑ [83] Reinstatement of drug-seeking behavior ↑ ↑ ↓ ↓ [83] Neurochemical plasticity CREBTooltip cAMP response element-binding protein phosphorylation in the nucleus accumbens ↓ ↓ ↓ ↓ ↓ [83] Sensitized dopamine response in the nucleus accumbens No Yes No Yes [83] Altered striatal dopamine signaling ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD1, ↓DRD2, ↑DRD3 ↑DRD2 ↑DRD2 [83] Altered striatal opioid signaling No change or ↑μ-opioid receptors ↑μ-opioid receptors ↑κ-opioid receptors ↑μ-opioid receptors ↑μ-opioid receptors No change No change [83] Changes in striatal opioid peptides ↑dynorphin No change: enkephalin ↑dynorphin ↓enkephalin ↑dynorphin ↑dynorphin [83] Mesocorticolimbic synaptic plasticity Number of dendrites in the nucleus accumbens ↓ ↑ ↑ [83] Dendritic spine density in the nucleus accumbens ↓ ↑ ↑ [83]

### Neonatal

Unlike other drugs, babies with [prenatal exposure to methamphetamine](/source/Drugs_in_pregnancy#Methamphetamine) do not show immediate signs of withdrawal. Instead, cognitive and behavioral problems start emerging when the children reach school age.[108]

A [prospective cohort study](/source/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](/source/Externalizing_disorder) and attention deficit hyperactivity disorder (ADHD).[109]

## 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.[5][27] 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](/source/Cardiac_dysrhythmia), confusion, [difficult or painful urination](/source/Dysuria), high or low blood pressure, [high body temperature](/source/Hyperthermia), [over-active or over-responsive reflexes](/source/Hyperreflexia), [muscle aches](/source/Myalgia), severe [agitation](/source/Psychomotor_agitation), [rapid breathing](/source/Tachypnea), [tremor](/source/Tremor), [urinary hesitancy](/source/Urinary_hesitancy), and [an inability to pass urine](/source/Urinary_retention).[5][48] An extremely large overdose may produce symptoms such as [adrenergic storm](/source/Adrenergic_storm), [methamphetamine psychosis](/source/Methamphetamine_psychosis), [substantially reduced or no urine output](/source/Anuria), [cardiogenic shock](/source/Cardiogenic_shock), [bleeding in the brain](/source/Cerebral_hemorrhage), [circulatory collapse](/source/Circulatory_collapse), [hyperpyrexia](/source/Hyperpyrexia) (i.e., dangerously high body temperature), [pulmonary hypertension](/source/Pulmonary_hypertension), [kidney failure](/source/Kidney_failure), [rapid muscle breakdown](/source/Rhabdomyolysis), [serotonin syndrome](/source/Serotonin_syndrome), and a form of [stereotypy](/source/Stereotypy#Associated_terms) ("tweaking").[sources 1] A methamphetamine overdose will likely also result in mild [brain damage](/source/Brain_damage) owing to [dopaminergic](/source/Dopaminergic) and [serotonergic](/source/Serotonin) neurotoxicity.[113][34] Death from methamphetamine poisoning is typically preceded by convulsions and [coma](/source/Coma).[27]

### Psychosis

Main section: [Stimulant psychosis § Substituted amphetamines](/source/Stimulant_psychosis#Substituted_amphetamines)

Use of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g., [paranoia](/source/Paranoia), [hallucinations](/source/Hallucination), [delirium](/source/Delirium), and [delusions](/source/Delusion)).[5][114] A [Cochrane Collaboration](/source/Cochrane_Collaboration) review on treatment for amphetamine, dextroamphetamine, and methamphetamine use-induced psychosis states that about 5–15% of users fail to recover completely.[114][115] The same review asserts that, based upon at least one trial, [antipsychotic](/source/Antipsychotic) medications effectively resolve the symptoms of acute amphetamine psychosis.[114] Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[116]

### 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.[117] 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.[118] Unlike fentanyl which causes respiratory depression, methamphetamine is not a respiratory depressant. Some deaths are as a result of intracranial hemorrhage[119] and some deaths are cardiovascular in nature including flash pulmonary edema[120] and ventricular fibrillation.[121][122]

### Emergency treatment

Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of [activated charcoal](/source/Activated_charcoal) and [sedation](/source/Sedation).[5] There is not enough evidence on [hemodialysis](/source/Hemodialysis) or [peritoneal dialysis](/source/Peritoneal_dialysis) in cases of methamphetamine intoxication to determine their usefulness.[27] [Forced acid diuresis](/source/Forced_acid_diuresis) (e.g., with [vitamin C](/source/Vitamin_C)) will increase methamphetamine excretion but is not recommended as it may increase the risk of aggravating acidosis, or cause seizures or rhabdomyolysis.[5] Hypertension presents a risk for [intracranial hemorrhage](/source/Intracranial_hemorrhage) (i.e., bleeding in the brain) and, if severe, is typically treated with intravenous [phentolamine](/source/Phentolamine) or [nitroprusside](/source/Nitroprusside).[5] Blood pressure often drops gradually following sufficient sedation with a [benzodiazepine](/source/Benzodiazepine) and providing a calming environment.[5]

Antipsychotics such as [haloperidol](/source/Haloperidol) are useful in treating agitation and psychosis from methamphetamine overdose.[123][124] [Beta blockers](/source/Beta_blocker) with lipophilic properties and CNS penetration such as [metoprolol](/source/Metoprolol) and [labetalol](/source/Labetalol) may be useful for treating CNS and cardiovascular toxicity.[125][126] The mixed [alpha-](/source/Alpha_blocker) and [beta-blocker](/source/Beta-blocker) labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.[123] The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.[123]

## Interactions

Methamphetamine is metabolized by the liver enzyme CYP2D6, so [CYP2D6 inhibitors](/source/CYP2D6#Ligands) will prolong the [elimination half-life](/source/Elimination_half-life) of methamphetamine.[27][127] Methamphetamine also interacts with [monoamine oxidase inhibitors](/source/Monoamine_oxidase_inhibitor) (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous.[27] Methamphetamine may decrease the effects of [sedatives](/source/Sedative) and [depressants](/source/Depressant) and increase the effects of [antidepressants](/source/Antidepressant) and other stimulants as well.[27] Methamphetamine may counteract the effects of [antihypertensives](/source/Antihypertensive) and [antipsychotics](/source/Antipsychotic) owing to its effects on the cardiovascular system and cognition respectively.[27] The [pH](/source/PH) of gastrointestinal content and urine affects the absorption and excretion of methamphetamine.[27] Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite.[27] Owing to the effect pH has on absorption, [proton pump inhibitors](/source/Proton_pump_inhibitor), which reduce [gastric acid](/source/Gastric_acid), are known to interact with methamphetamine.[27] [Norepinephrine reuptake inhibitors](/source/Norepinephrine_reuptake_inhibitor) (NRIs) like [atomoxetine](/source/Atomoxetine) prevent [norepinephrine](/source/Norepinephrine) release induced by amphetamines and have been found to reduce the stimulant, euphoriant, and [sympathomimetic](/source/Sympathomimetic) effects of [dextroamphetamine](/source/Dextroamphetamine) in humans.[128][129][130] Similarly, [norepinephrine–dopamine reuptake inhibitors](/source/Norepinephrine%E2%80%93dopamine_reuptake_inhibitor) (NRIs) like [methylphenidate](/source/Methylphenidate) and [bupropion](/source/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.[131][129][132][133]

## Pharmacology

### Pharmacodynamics

Monoamine release of methamphetamine and related agents (EC50Tooltip Half maximal effective concentration, nM) Compound NETooltip Norepinephrine DATooltip Dopamine 5-HTTooltip Serotonin Ref Phenethylamine 10.9 39.5 >10,000 [134][135][136] d-Amphetamine 6.6–7.2 5.8–24.8 698–1,765 [137][138] l-Amphetamine 9.5 27.7 ND [135][136] d-Methamphetamine 12.3–13.8 8.5–24.5 736–1,292 [137][139] l-Methamphetamine 28.5 416 4,640 [137] d-Ethylamphetamine 28.8 44.1 333.0 [140][141] Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The assays were done in rat brain synaptosomes and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs:[142][143]

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

Methamphetamine has been identified as a potent [full agonist](/source/Full_agonist) of [trace amine-associated receptor 1](/source/TAAR1) (TAAR1), a [G protein-coupled receptor](/source/G_protein-coupled_receptor) (GPCR) that regulates brain [catecholamine](/source/Catecholamine) systems.[144][145] Activation of TAAR1 increases [cyclic adenosine monophosphate](/source/Cyclic_adenosine_monophosphate) (cAMP) production and either completely inhibits or reverses the transport direction of the [dopamine transporter](/source/Dopamine_transporter) (DAT), [norepinephrine transporter](/source/Norepinephrine_transporter) (NET), and [serotonin transporter](/source/Serotonin_transporter) (SERT).[144][146] When methamphetamine binds to TAAR1, it triggers transporter [phosphorylation](/source/Phosphorylation) via [protein kinase A](/source/Protein_kinase_A) (PKA) and [protein kinase C](/source/Protein_kinase_C) (PKC) signaling, ultimately resulting in the [internalization](/source/Endocytosis) or reverse function of [monoamine transporters](/source/Monoamine_transporter).[144][147] Methamphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a [Ca2+/calmodulin-dependent protein kinase](/source/Ca2%2B%2Fcalmodulin-dependent_protein_kinase) (CAMK)-dependent signaling pathway, in turn producing dopamine efflux.[148][149][150] TAAR1 has been shown to reduce the [firing rate](/source/Action_potential) of neurons through direct activation of [G protein-coupled inwardly-rectifying potassium channels](/source/G_protein-coupled_inwardly-rectifying_potassium_channel).[151][152][153] TAAR1 activation by methamphetamine in [astrocytes](/source/Astrocyte) appears to negatively modulate the membrane expression and function of [EAAT2](/source/EAAT2), a type of [glutamate transporter](/source/Glutamate_transporter).[66]

In addition to its effect on the plasma membrane monoamine transporters, methamphetamine inhibits synaptic vesicle function by inhibiting [VMAT2](/source/VMAT2), which prevents monoamine uptake into the vesicles and promotes their release.[154] Methamphetamine binds to VMAT2 via the [resperine](/source/Reserpine) site, in contrast to amphetamine, which appears to bind at the [tetrabenazine](/source/Tetrabenazine) site.[155] This results in the outflow of monoamines from [synaptic vesicles](/source/Synaptic_vesicle) into the [cytosol](/source/Cytosol) (intracellular fluid) of the [presynaptic neuron](/source/Presynaptic_neuron), and their subsequent release into the synaptic cleft by the phosphorylated transporters.[156] Other [transporters](/source/Membrane_transport_protein) that methamphetamine is known to inhibit are [SLC22A3](/source/SLC22A3) and [SLC22A5](/source/SLC22A5).[154] SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity [carnitine](/source/Carnitine) transporter.[145][157]

Methamphetamine is also an [agonist](/source/Agonist) of the [alpha-2 adrenergic receptors](/source/Alpha-2_adrenergic_receptor) and [sigma receptors](/source/Sigma_receptor) with a greater [affinity](/source/Binding_affinity) for [σ1](/source/Sigma-1_receptor) than [σ2](/source/Sigma-2_receptor), and inhibits [monoamine oxidase A](/source/Monoamine_oxidase_A) (MAO-A) and [monoamine oxidase B](/source/Monoamine_oxidase_B) (MAO-B).[64][145][68] Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain.[64][68] [Dextromethamphetamine](/source/Dextromethamphetamine) is a stronger [psychostimulant](/source/Psychostimulant), but [levomethamphetamine](/source/Levomethamphetamine) has stronger [peripheral](/source/Peripheral_nervous_system) effects, a longer half-life, and longer perceived effects among heavy substance users.[158][159][160] At high doses, both enantiomers of methamphetamine can induce similar [stereotypy](/source/Stereotypy) and [methamphetamine psychosis](/source/Methamphetamine_psychosis),[159] but levomethamphetamine has shorter psychodynamic effects.[160]

### Pharmacokinetics

The [bioavailability](/source/Bioavailability) of methamphetamine is 67% [orally](/source/Oral_administration), 79% intranasally, 67 to 90% via [inhalation](/source/Inhalational_administration) ([smoking](/source/Smoking)), and 100% intravenously.[4][5][6] 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.[161] Methamphetamine is also well absorbed following inhalation and following intranasal administration.[5] Because of the high [lipophilicity](/source/Lipophilicity) of methamphetamine due to its methyl group, it can readily move through the [blood–brain barrier](/source/Blood%E2%80%93brain_barrier) faster than other stimulants, where it is more resistant to degradation by [monoamine oxidase](/source/Monoamine_oxidase).[5][161][162] The amphetamine metabolite peaks at 10–24 hours.[5] Methamphetamine is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH.[27][161] When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine.[161] Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine.[161] The [elimination half-life](/source/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.[5][4] The elimination half-life of methamphetamine does not vary by [route of administration](/source/Route_of_administration), but is subject to substantial [interindividual variability](/source/Interindividual_variability).[4]

CYP2D6, [dopamine β-hydroxylase](/source/Dopamine_%CE%B2-hydroxylase), [flavin-containing monooxygenase 3](/source/Flavin-containing_monooxygenase_3), [butyrate-CoA ligase](/source/Butyrate-CoA_ligase), and [glycine N-acyltransferase](/source/Glycine_N-acyltransferase) are the enzymes known to metabolize methamphetamine or its metabolites in humans.[sources 2] The primary metabolites are amphetamine and [4-hydroxymethamphetamine](/source/Pholedrine);[161] other minor metabolites include: [4-hydroxyamphetamine](/source/4-hydroxyamphetamine), [4-hydroxynorephedrine](/source/4-hydroxynorephedrine), [4-hydroxyphenylacetone](/source/4-hydroxyphenylacetone), [benzoic acid](/source/Benzoic_acid), [hippuric acid](/source/Hippuric_acid), [norephedrine](/source/Norephedrine), and [phenylacetone](/source/Phenylacetone), the metabolites of amphetamine.[11][161][163] Among these metabolites, the active [sympathomimetics](/source/Sympathomimetics) are amphetamine, 4‑hydroxyamphetamine,[169] 4‑hydroxynorephedrine,[170] 4-hydroxymethamphetamine,[161] and norephedrine.[171] Methamphetamine is a CYP2D6 inhibitor.[127]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[11][161][172] The known metabolic pathways include:

Metabolic pathways of methamphetamine in humans[sources 2] Methamphetamine 4-Hydroxymethamphetamine 4-Hydroxyphenylacetone Phenylacetone Benzoic acid Hippuric acid Amphetamine Norephedrine 4-Hydroxyamphetamine 4-Hydroxynorephedrine The primary metabolites of methamphetamine are amphetamine and 4-hydroxymethamphetamine.[161] Human microbiota, particularly Lactobacillus, Enterococcus, and Clostridium species, contribute to the metabolism of methamphetamine via an enzyme which N-demethylates methamphetamine and 4-hydroxymethamphetamine into amphetamine and 4-hydroxyamphetamine respectively.[173][174]

#### Detection in biological fluids

Methamphetamine and amphetamine are often measured in urine or blood as part of a [drug test](/source/Drug_test) for sports, employment, poisoning diagnostics, and forensics.[175][176][177][178] 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.[179] Chiral separation is needed to assess the possible contribution of [levomethamphetamine](/source/Levomethamphetamine), which is an active ingredients in some OTC nasal decongestants,[note 4] toward a positive test result.[179][180][181] Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.[182]

## Chemistry

Shards of pure methamphetamine hydrochloride, also known as crystal meth

Methamphetamine is a [chiral](/source/Chirality_(chemistry)) compound with two enantiomers, [dextromethamphetamine](/source/Dextromethamphetamine) and [levomethamphetamine](/source/Levomethamphetamine). At room temperature, the [free base](/source/Free_base) of methamphetamine is a clear and colorless liquid with an odor characteristic of [geranium](/source/Geranium) leaves.[14] It is [soluble](/source/Soluble) in [diethyl ether](/source/Diethyl_ether) and [ethanol](/source/Ethanol) as well as [miscible](/source/Miscible) with [chloroform](/source/Chloroform).[14]

Chemical structures of methamphetamine enantiomers

		- [Dextromethamphetamine](/source/Dextromethamphetamine)

		- [Levomethamphetamine](/source/Levomethamphetamine)

In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste.[14] 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](/source/Crystallinity) powder.[14] The hydrochloride salt is also freely soluble in ethanol and water.[14] The crystal structure of either enantiomer is [monoclinic](/source/Monoclinic) with P21 [space group](/source/Space_group); at 90 K (−183.2 °C; −297.7 °F), it has [lattice parameters](/source/Lattice_parameter) *a* = 7.10 [Å](/source/Angstrom), *b* = 7.29 Å, *c* = 10.81 Å, and *β* = 97.29°.[183]

### Degradation

A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration.[184] A year-long study (also from 2011) showed that methamphetamine in soils is a persistent pollutant.[185] In a 2013 study of bioreactors in [wastewater](/source/Wastewater), methamphetamine was found to be largely degraded within 30 days under exposure to light.[186]

### Synthesis

Further information on illicit amphetamine synthesis: [History and culture of substituted amphetamines § Illegal synthesis](/source/History_and_culture_of_substituted_amphetamines#Illegal_synthesis)

[Racemic](/source/Racemic) methamphetamine may be prepared starting from [phenylacetone](/source/Phenylacetone) by either the [Leuckart](/source/Leuckart_reaction)[187] or [reductive amination](/source/Reductive_amination) methods.[188] In the Leuckart reaction, one equivalent of phenylacetone is reacted with two equivalents of [*N*-methylformamide](/source/N-methylformamide) to produce the formyl [amide](/source/Amide) of methamphetamine plus carbon dioxide and [methylamine](/source/Methylamine) as side products.[188] In this reaction, an [iminium](/source/Iminium) cation is formed as an intermediate which is [reduced](/source/Redox) by the second equivalent of *N*-methylformamide.[188] The intermediate formyl amide is then [hydrolyzed](/source/Hydrolyzed) under acidic aqueous conditions to yield methamphetamine as the final product.[188] Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.[188]

Methamphetamine synthesis

Method of methamphetamine synthesis of methamphetamine via [reductive amination](/source/Reductive_amination)

Methods of methamphetamine synthesis via the [Leuckart reaction](/source/Leuckart_reaction)

## History, society, and culture

Main article: [History and culture of substituted amphetamines](/source/History_and_culture_of_substituted_amphetamines)

Pervitin, a methamphetamine brand used by German soldiers during [World War II](/source/World_War_II), was dispensed in various forms, including tablet containers.

U.S. [drug overdose](/source/Drug_overdose) related fatalities in 2017 were 70,200, including 10,333 of those related to psychostimulants (including methamphetamine).[189][190]

Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist [Lazăr Edeleanu](/source/Laz%C4%83r_Edeleanu) who named it *phenylisopropylamine*.[191][192] Shortly after, methamphetamine was synthesized from [ephedrine](/source/Ephedrine) in 1893 by Japanese [chemist](/source/Chemist) [Nagai Nagayoshi](/source/Nagai_Nagayoshi).[193] Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist [Akira Ogata](/source/Akira_Ogata) via [reduction](/source/Redox) of ephedrine using red [phosphorus](/source/Phosphorus) and [iodine](/source/Iodine).[194]

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](/source/Temmler) pharmaceutical company.[195][196] It was used by all branches of the combined [armed forces](/source/Wehrmacht) of the [Third Reich](/source/Third_Reich), for its stimulant effects and to induce extended [wakefulness](/source/Wakefulness).[197][198] Pervitin became colloquially known among the German troops as "[Stuka](/source/Stuka)-Tablets" (*Stuka-Tabletten*) and "[Herman-Göring](/source/Hermann_G%C3%B6ring)-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.[199] 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.[199] At the end of the war, it was used as part of a new drug: [D-IX](/source/D-IX).

[Obetrol](/source/Obetrol), patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of [obesity](/source/Obesity), was one of the first brands of pharmaceutical methamphetamine products.[200] Because of the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in the United States in the 1950s and 1960s.[200] Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.[192] For example, during the early 1970s in the United States, methamphetamine became a [schedule II controlled substance](/source/Controlled_Substances_Act#Schedule_II_controlled_substances) under the [Controlled Substances Act](/source/Controlled_Substances_Act).[3] As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.[201]

## Trafficking

The [Golden Triangle (Southeast Asia)](/source/Golden_Triangle_(Southeast_Asia)), specifically [Shan State](/source/Shan_State), Myanmar, is the world's leading producer of methamphetamine as production has shifted to [*ya ba*](/source/Yaba_(drug)) and crystalline methamphetamine, including for export to the United States and across East and Southeast Asia and the Pacific.[202]

Concerning the accelerating synthetic drug production in the region, the Cantonese Chinese syndicate [Sam Gor](/source/Sam_Gor), also known as The Company, is understood to be the main international crime syndicate responsible for this shift.[203] 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.[204] Sam Gor is alleged to control 40% of the Asia-Pacific methamphetamine market, while also trafficking [heroin](/source/Heroin) and [ketamine](/source/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.[205] The group is understood to be headed by [Tse Chi Lop](/source/Tse_Chi_Lop), a gangster born in [Guangzhou](/source/Guangzhou), [China](/source/China) who also holds a Canadian passport.

[Liu Zhaohua](/source/Liu_Zhaohua) was another individual involved in the production and trafficking of methamphetamine until his arrest in 2005.[206] It was estimated over 18 tonnes of methamphetamine were produced under his watch.[206]

## Legal status

Main article: [Legal status of methamphetamine](/source/Legal_status_of_methamphetamine)

The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many [jurisdictions](/source/Jurisdiction).[207][208] In some jurisdictions, it is legally available as a prescription medication. Methamphetamine has been placed in schedule II of the [United Nations](/source/United_Nations) [Convention on Psychotropic Substances](/source/Convention_on_Psychotropic_Substances) treaty, indicating that it has limited medical use.[208]

## Research

Animal models have shown that low-dose methamphetamine improves cognitive and behavioural functioning following TBI (traumatic brain injury).[7] 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.[209] It has also been found that TBI patients testing positive for methamphetamine at the time of emergency department admission have lower rates of mortality.[210]

It has been suggested, based on animal research, that calcitriol, the active metabolite of [vitamin D](/source/Vitamin_D), can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of methamphetamine.[211] Protection against methamphetamine-induced neurotoxicity has also been observed following administration of ascorbic acid (vitamin C),[212] cobalamin (vitamin B12),[213] and vitamin E.[214]

## See also

- [18-MC](/source/18-Methoxycoronaridine) – Chemical compound

- *[Breaking Bad](/source/Breaking_Bad)* – TV drama series centered on illicit methamphetamine synthesis

- [Drug checking](/source/Drug_checking) – Harm reduction technique

- [Faces of Meth](/source/Faces_of_Meth) – Drug prevention project

- [Famprofazone](/source/Famprofazone) – Non-steroidal anti-inflammatory drug yielding methamphetamine as a major metabolite

- [Harm reduction](/source/Harm_reduction) – Public health policies which lessen negative aspects of problematic activities

- [Methamphetamine and Native Americans](/source/Methamphetamine_and_Native_Americans)

- [Methamphetamine in Australia](/source/Methamphetamine_use_in_Australia)

- [Methamphetamine in Bangladesh](/source/Methamphetamine_in_Bangladesh) – Illegal mix of methamphetamine and caffeine

- [Methamphetamine in the Philippines](/source/Illegal_drug_trade_in_the_Philippines#Methamphetamine_production)

- [Methamphetamine in the United States](/source/Methamphetamine_in_the_United_States)

- [Montana Meth Project](/source/Montana_Meth_Project) – Montana-based organization aiming to reduce meth use among teenagers

- [Recreational drug use](/source/Recreational_drug_use) – Use of drugs with the primary intention to alter the state of consciousness

- [Rolling meth lab](/source/Rolling_meth_lab) – A transportable laboratory that is used to illegally produce methamphetamine

- [Ya ba](/source/Ya_ba) – Southeast Asian tablets containing a mixture of methamphetamine and caffeine

## Footnotes

1. **[^](#cite_ref-76)** [Ion channel](/source/Ion_channel) [G proteins](/source/G_proteins) & [linked receptors](/source/G_protein-coupled_receptor) (Text color) [Transcription factors](/source/Transcription_factor)

1. **[^](#cite_ref-25)** *Methamphetamine* is contracted from ***N*-methylamphetamine**. Synonyms and alternate spellings include: ***N*-methylamphetamine**, **desoxyephedrine**, **Syndrox**, **Methedrine**, and **Desoxyn**.[15][16][17] Common slang names 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]

1. **[^](#cite_ref-28)** 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](/source/International_Nonproprietary_Name) [INN]) and D-methamphetamine, (*S*)-methamphetamine, or metamfetamine ([INN](/source/International_Nonproprietary_Name)), respectively.[15][26]

1. ^ [***a***](#cite_ref-D-meth_FDA_label_30-0) [***b***](#cite_ref-D-meth_FDA_label_30-1) The [medication package insert](/source/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](/source/Stereochemical) ambiguity.[27]

1. ^ [***a***](#cite_ref-OTC_levmetamfetamine_34-0) [***b***](#cite_ref-OTC_levmetamfetamine_34-1) [***c***](#cite_ref-OTC_levmetamfetamine_34-2) The active ingredient in some OTC inhalers in the United States is listed as *levmetamfetamine*, the [INN](/source/International_Nonproprietary_Name) and [USAN](/source/United_States_Adopted_Name) of levomethamphetamine.[29][30]

1. **[^](#cite_ref-87)** Transcription factors are proteins that increase or decrease the [expression](/source/Gene_expression) of specific genes.[81]

1. **[^](#cite_ref-88)** 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.

1. **[^](#cite_ref-95)** 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.

## Reference notes

1. **[^](#cite_ref-121)** [5][27][48][58][110][111][112]

1. ^ [***a***](#cite_ref-methamphetamine_metabolism_178-0) [***b***](#cite_ref-methamphetamine_metabolism_178-1) [10][11][12][13][161][163][164][165][166][167][168]

## References

1. **[^](#cite_ref-1)** ["methamphetamine"](https://web.archive.org/web/20210614004641/https://www.lexico.com/en/definition/methamphetamine). *Methamphetamine*. *Lexico*. Archived from [the original](https://www.lexico.com/en/definition/methamphetamine) on 14 June 2021. Retrieved 22 April 2022.

1. **[^](#cite_ref-2)** [Anvisa](/source/Brazilian_Health_Regulatory_Agency) (24 July 2023). ["RDC Nº 804 – Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial"](https://web.archive.org/web/20230827163149/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451) [Collegiate Board Resolution No. 804 – Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). [Diário Oficial da União](/source/Di%C3%A1rio_Oficial_da_Uni%C3%A3o) (published 25 July 2023). Archived from [the original](https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-804-de-24-de-julho-de-2023-498447451) on 27 August 2023. Retrieved 27 November 2025.

1. ^ [***a***](#cite_ref-:USAS2_3-0) [***b***](#cite_ref-:USAS2_3-1) [***c***](#cite_ref-:USAS2_3-2) Ingersoll J (7 July 1971). ["Amphetamine, Methamphetamine, and Optical Isomers"](https://archives.federalregister.gov/issue_slice/1971/7/7/12730-12734.pdf) (PDF). *[Federal Register](/source/Federal_Register)*. Bureau of Narcotics and Dangerous Drugs. [Archived](https://web.archive.org/web/20241204092650/https://archives.federalregister.gov/issue_slice/1971/7/7/12730-12734.pdf) (PDF) from the original on 4 December 2024. Retrieved 27 November 2024.

1. ^ [***a***](#cite_ref-pmid19426289_4-0) [***b***](#cite_ref-pmid19426289_4-1) [***c***](#cite_ref-pmid19426289_4-2) [***d***](#cite_ref-pmid19426289_4-3) [***e***](#cite_ref-pmid19426289_4-4) [***f***](#cite_ref-pmid19426289_4-5) [***g***](#cite_ref-pmid19426289_4-6) [***h***](#cite_ref-pmid19426289_4-7) [***i***](#cite_ref-pmid19426289_4-8) [***j***](#cite_ref-pmid19426289_4-9) [***k***](#cite_ref-pmid19426289_4-10) [***l***](#cite_ref-pmid19426289_4-11) [***m***](#cite_ref-pmid19426289_4-12) [***n***](#cite_ref-pmid19426289_4-13) Cruickshank CC, Dyer KR (July 2009). ["A review of the clinical pharmacology of methamphetamine"](https://doi.org/10.1111%2Fj.1360-0443.2009.02564.x). *Addiction*. **104** (7): 1085–1099. [doi](/source/Doi_(identifier)):[10.1111/j.1360-0443.2009.02564.x](https://doi.org/10.1111%2Fj.1360-0443.2009.02564.x). [PMID](/source/PMID_(identifier)) [19426289](https://pubmed.ncbi.nlm.nih.gov/19426289).

1. ^ [***a***](#cite_ref-Schep_5-0) [***b***](#cite_ref-Schep_5-1) [***c***](#cite_ref-Schep_5-2) [***d***](#cite_ref-Schep_5-3) [***e***](#cite_ref-Schep_5-4) [***f***](#cite_ref-Schep_5-5) [***g***](#cite_ref-Schep_5-6) [***h***](#cite_ref-Schep_5-7) [***i***](#cite_ref-Schep_5-8) [***j***](#cite_ref-Schep_5-9) [***k***](#cite_ref-Schep_5-10) [***l***](#cite_ref-Schep_5-11) [***m***](#cite_ref-Schep_5-12) [***n***](#cite_ref-Schep_5-13) [***o***](#cite_ref-Schep_5-14) [***p***](#cite_ref-Schep_5-15) [***q***](#cite_ref-Schep_5-16) [***r***](#cite_ref-Schep_5-17) Schep LJ, Slaughter RJ, Beasley DM (August 2010). "The clinical toxicology of metamfetamine". *Clinical Toxicology*. **48** (7): 675–694. [doi](/source/Doi_(identifier)):[10.3109/15563650.2010.516752](https://doi.org/10.3109%2F15563650.2010.516752). [PMID](/source/PMID_(identifier)) [20849327](https://pubmed.ncbi.nlm.nih.gov/20849327).

1. ^ [***a***](#cite_ref-pmid25176528_6-0) [***b***](#cite_ref-pmid25176528_6-1) [***c***](#cite_ref-pmid25176528_6-2) [***d***](#cite_ref-pmid25176528_6-3) Courtney KE, Ray LA (October 2014). ["Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164186). *Drug Alcohol Depend*. **143**: 11–21. [doi](/source/Doi_(identifier)):[10.1016/j.drugalcdep.2014.08.003](https://doi.org/10.1016%2Fj.drugalcdep.2014.08.003). [PMC](/source/PMC_(identifier)) [4164186](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164186). [PMID](/source/PMID_(identifier)) [25176528](https://pubmed.ncbi.nlm.nih.gov/25176528).

1. ^ [***a***](#cite_ref-pmid25724762_7-0) [***b***](#cite_ref-pmid25724762_7-1) [***c***](#cite_ref-pmid25724762_7-2) [***d***](#cite_ref-pmid25724762_7-3) [***e***](#cite_ref-pmid25724762_7-4) Rau T, Ziemniak J, Poulsen D (January 2016). ["The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury"](https://doi.org/10.1016%2Fj.pnpbp.2015.02.013). *Progress in Neuro-psychopharmacology & Biological Psychiatry*. **64**: 231–236. [doi](/source/Doi_(identifier)):[10.1016/j.pnpbp.2015.02.013](https://doi.org/10.1016%2Fj.pnpbp.2015.02.013). [PMID](/source/PMID_(identifier)) [25724762](https://pubmed.ncbi.nlm.nih.gov/25724762).

1. **[^](#cite_ref-Pubchem1_8-0)** ["Methamphetamine: Toxicity"](https://pubchem.ncbi.nlm.nih.gov/compound/1206#section=Toxicity). *PubChem Compound*. National Center for Biotechnology Information. [Archived](https://web.archive.org/web/20150104182703/https://pubchem.ncbi.nlm.nih.gov/compound/1206#section=Toxicity) from the original on 4 January 2015. Retrieved 4 January 2015.

1. **[^](#cite_ref-9)** [https://go.drugbank.com/drugs/DB01577#:~:text=hydroxynorephedrine.-,Metamfetamine,Dextroamphetamine,-Route](https://go.drugbank.com/drugs/DB01577#:~:text=hydroxynorephedrine.-,Metamfetamine,Dextroamphetamine,-Route)

1. ^ [***a***](#cite_ref-Methamphetamine_–_p-hydroxymethamphetamine_CYP2D6_review_10-0) [***b***](#cite_ref-Methamphetamine_–_p-hydroxymethamphetamine_CYP2D6_review_10-1) Sellers EM, Tyndale RF (2000). "Mimicking gene defects to treat drug dependence". *Ann. N. Y. Acad. Sci*. **909** (1): 233–246. [Bibcode](/source/Bibcode_(identifier)):[2000NYASA.909..233S](https://ui.adsabs.harvard.edu/abs/2000NYASA.909..233S). [doi](/source/Doi_(identifier)):[10.1111/j.1749-6632.2000.tb06685.x](https://doi.org/10.1111%2Fj.1749-6632.2000.tb06685.x). [PMID](/source/PMID_(identifier)) [10911933](https://pubmed.ncbi.nlm.nih.gov/10911933). Methamphetamine, a central nervous system stimulant drug, is p-hydroxylated by CYP2D6 to less active p-OH-methamphetamine.

1. ^ [***a***](#cite_ref-FDA_Pharmacokinetics_11-0) [***b***](#cite_ref-FDA_Pharmacokinetics_11-1) [***c***](#cite_ref-FDA_Pharmacokinetics_11-2) [***d***](#cite_ref-FDA_Pharmacokinetics_11-3) ["Adderall XR Prescribing Information"](https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf) (PDF). *United States Food and Drug Administration*. Shire US Inc. December 2013. pp. 12–13. [Archived](https://web.archive.org/web/20131230233702/http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021303s026lbl.pdf) (PDF) from the original on 30 December 2013. Retrieved 30 December 2013.

1. ^ [***a***](#cite_ref-FMO_12-0) [***b***](#cite_ref-FMO_12-1) Table 5 in: Krueger SK, Williams DE (June 2005). ["Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602). *Pharmacology & Therapeutics*. **106** (3): 357–387. [doi](/source/Doi_(identifier)):[10.1016/j.pharmthera.2005.01.001](https://doi.org/10.1016%2Fj.pharmthera.2005.01.001). [PMC](/source/PMC_(identifier)) [1828602](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828602). [PMID](/source/PMID_(identifier)) [15922018](https://pubmed.ncbi.nlm.nih.gov/15922018).

1. ^ [***a***](#cite_ref-FMO3-Primary_13-0) [***b***](#cite_ref-FMO3-Primary_13-1) Cashman JR, Xiong YN, Xu L, Janowsky A (March 1999). "N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication". *J. Pharmacol. Exp. Ther*. **288** (3): 1251–1260. [doi](/source/Doi_(identifier)):[10.1016/S0022-3565(24)38081-4](https://doi.org/10.1016%2FS0022-3565%2824%2938081-4). [PMID](/source/PMID_(identifier)) [10027866](https://pubmed.ncbi.nlm.nih.gov/10027866).

1. ^ [***a***](#cite_ref-Pubchem2_14-0) [***b***](#cite_ref-Pubchem2_14-1) [***c***](#cite_ref-Pubchem2_14-2) [***d***](#cite_ref-Pubchem2_14-3) [***e***](#cite_ref-Pubchem2_14-4) [***f***](#cite_ref-Pubchem2_14-5) [***g***](#cite_ref-Pubchem2_14-6) ["Methamphetamine: Chemical and Physical Properties"](https://pubchem.ncbi.nlm.nih.gov/compound/1206#section=Chemical-and-Physical-Properties). *PubChem Compound*. National Center for Biotechnology Information. [Archived](https://web.archive.org/web/20150104182703/https://pubchem.ncbi.nlm.nih.gov/compound/1206#section=Chemical-and-Physical-Properties) from the original on 4 January 2015. Retrieved 4 January 2015.

1. ^ [***a***](#cite_ref-EMCDDA_profile_15-0) [***b***](#cite_ref-EMCDDA_profile_15-1) ["Methamphetamine"](http://www.emcdda.europa.eu/publications/drug-profiles/methamphetamine). *Drug profiles*. [European Monitoring Centre for Drugs and Drug Addiction](/source/European_Monitoring_Centre_for_Drugs_and_Drug_Addiction) (EMCDDA). 8 January 2015. [Archived](https://web.archive.org/web/20160415220149/http://www.emcdda.europa.eu/publications/drug-profiles/methamphetamine) from the original on 15 April 2016. Retrieved 27 November 2018. The term metamfetamine (the International Non-Proprietary Name: INN) strictly relates to the specific enantiomer (S)-N,α-dimethylbenzeneethanamine.

1. **[^](#cite_ref-DB_ID_16-0)** ["Methamphetamine: Identification"](http://www.drugbank.ca/drugs/DB01577#identification). *DrugBank*. University of Alberta. 8 February 2013. [Archived](https://web.archive.org/web/20151228164940/http://www.drugbank.ca/drugs/DB01577#identification) from the original on 28 December 2015. Retrieved 1 January 2014.

1. **[^](#cite_ref-17)** ["Methedrine (methamphetamine hydrochloride): Uses, Symptoms, Signs and Addiction Treatment"](http://addictionlibrary.org/prescription/methedrine.html). *Addictionlibrary.org*. [Archived](https://web.archive.org/web/20160304045442/http://addictionlibrary.org/prescription/methedrine.html) from the original on 4 March 2016. Retrieved 16 January 2016.

1. **[^](#cite_ref-18)** ["Polisi Tangkap Bandar Shabu-shabu"](https://news.detik.com/berita/d-356478/polisi-tangkap-bandar-shabu-shabu). *Detik News* (in Indonesian). [Archived](https://web.archive.org/web/20230729143513/https://news.detik.com/berita/d-356478/polisi-tangkap-bandar-shabu-shabu) from the original on 29 July 2023. Retrieved 29 July 2023.

1. **[^](#cite_ref-19)** ["P1-M shabu seized from 3 drug pushers"](https://mb.com.ph/2023/7/26/p1-m-shabu-seized-from-3-drug-pushers). *Manila Bulletin*. 26 July 2023. Retrieved 29 July 2023.

1. **[^](#cite_ref-20)** ["Jadi pengedar sabu seorang IRT di Pidoli Dolok ditangkap Polisi – ANTARA News Sumatera Utara"](https://sumut.antaranews.com/berita/538872/jadi-pengedar-sabu-seorang-irt-di-pidoli-dolok-ditangkap-polisi). *ANTARA News Agency*. [Archived](https://web.archive.org/web/20240922021108/https://sumut.antaranews.com/berita/538872/jadi-pengedar-sabu-seorang-irt-di-pidoli-dolok-ditangkap-polisi) from the original on 22 September 2024. Retrieved 29 July 2023.

1. **[^](#cite_ref-21)** Marantal RD. ["E-bike driver nabbed in drug bust, shabu worth almost P1 million seized"](https://www.philstar.com/the-freeman/cebu-news/2023/06/02/2270858/e-bike-driver-nabbed-drug-bust-shabu-worth-almost-p1-million-seized). *Philstar.com*. [Archived](https://web.archive.org/web/20230729143513/https://www.philstar.com/the-freeman/cebu-news/2023/06/02/2270858/e-bike-driver-nabbed-drug-bust-shabu-worth-almost-p1-million-seized) from the original on 29 July 2023. Retrieved 29 July 2023.

1. **[^](#cite_ref-22)** ["Meth Slang Names"](https://web.archive.org/web/20131207185806/http://www.methhelponline.com/meth-slang.htm). *MethhelpOnline*. Archived from [the original](http://www.methhelponline.com/meth-slang.htm) on 7 December 2013. Retrieved 24 February 2026.

1. **[^](#cite_ref-23)** ["Methamphetamine"](https://web.archive.org/web/20220606183458/https://nida.nih.gov/research-topics/methamphetamine). *National Institute of Drug Abuse*. 20 November 2024. Archived from [the original](https://nida.nih.gov/research-topics/methamphetamine) on 6 June 2022. Retrieved 8 February 2025.

1. **[^](#cite_ref-24)** ["Methamphetamine and the law"](http://www.police.govt.nz/advice/drugs-and-alcohol/methamphetamine-and-law). [Archived](https://web.archive.org/web/20150128175632/http://www.police.govt.nz/advice/drugs-and-alcohol/methamphetamine-and-law) from the original on 28 January 2015. Retrieved 30 December 2014.

1. ^ [***a***](#cite_ref-d-meth_review_26-0) [***b***](#cite_ref-d-meth_review_26-1) [***c***](#cite_ref-d-meth_review_26-2) [***d***](#cite_ref-d-meth_review_26-3) [***e***](#cite_ref-d-meth_review_26-4) [***f***](#cite_ref-d-meth_review_26-5) [***g***](#cite_ref-d-meth_review_26-6) [***h***](#cite_ref-d-meth_review_26-7) Moszczynska A, Callan SP (September 2017). ["Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11047030). *The Journal of Pharmacology and Experimental Therapeutics*. **362** (3): 474–488. [doi](/source/Doi_(identifier)):[10.1124/jpet.116.238501](https://doi.org/10.1124%2Fjpet.116.238501). [PMC](/source/PMC_(identifier)) [11047030](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11047030). [PMID](/source/PMID_(identifier)) [28630283](https://pubmed.ncbi.nlm.nih.gov/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 (Procter & 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

1. **[^](#cite_ref-27)** ["Levomethamphetamine"](https://pubchem.ncbi.nlm.nih.gov/compound/36604). *Pubchem Compound*. National Center for Biotechnology Information. [Archived](https://web.archive.org/web/20141006215922/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604) from the original on 6 October 2014. Retrieved 27 November 2018.

1. ^ [***a***](#cite_ref-Desoxyn_FDA_label_29-0) [***b***](#cite_ref-Desoxyn_FDA_label_29-1) [***c***](#cite_ref-Desoxyn_FDA_label_29-2) [***d***](#cite_ref-Desoxyn_FDA_label_29-3) [***e***](#cite_ref-Desoxyn_FDA_label_29-4) [***f***](#cite_ref-Desoxyn_FDA_label_29-5) [***g***](#cite_ref-Desoxyn_FDA_label_29-6) [***h***](#cite_ref-Desoxyn_FDA_label_29-7) [***i***](#cite_ref-Desoxyn_FDA_label_29-8) [***j***](#cite_ref-Desoxyn_FDA_label_29-9) [***k***](#cite_ref-Desoxyn_FDA_label_29-10) [***l***](#cite_ref-Desoxyn_FDA_label_29-11) [***m***](#cite_ref-Desoxyn_FDA_label_29-12) [***n***](#cite_ref-Desoxyn_FDA_label_29-13) [***o***](#cite_ref-Desoxyn_FDA_label_29-14) [***p***](#cite_ref-Desoxyn_FDA_label_29-15) [***q***](#cite_ref-Desoxyn_FDA_label_29-16) [***r***](#cite_ref-Desoxyn_FDA_label_29-17) [***s***](#cite_ref-Desoxyn_FDA_label_29-18) [***t***](#cite_ref-Desoxyn_FDA_label_29-19) [***u***](#cite_ref-Desoxyn_FDA_label_29-20) [***v***](#cite_ref-Desoxyn_FDA_label_29-21) [***w***](#cite_ref-Desoxyn_FDA_label_29-22) [***x***](#cite_ref-Desoxyn_FDA_label_29-23) [***y***](#cite_ref-Desoxyn_FDA_label_29-24) [***z***](#cite_ref-Desoxyn_FDA_label_29-25) ["Desoxyn- methamphetamine hydrochloride tablet"](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=81bfc45f-c345-47d0-9fc9-77abe553b541). *DailyMed*. 8 September 2022. [Archived](https://web.archive.org/web/20240922021215/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=81bfc45f-c345-47d0-9fc9-77abe553b541) from the original on 22 September 2024. Retrieved 20 June 2024.

1. **[^](#cite_ref-Barkholtz_2023_31-0)** Barkholtz HM, Hadzima R, Miles A (July 2023). ["Pharmacology of R-(-)-Methamphetamine in Humans: A Systematic Review of the Literature"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10353062). *ACS Pharmacology & Translational Science*. **6** (7): 914–924. [doi](/source/Doi_(identifier)):[10.1021/acsptsci.3c00019](https://doi.org/10.1021%2Facsptsci.3c00019). [PMC](/source/PMC_(identifier)) [10353062](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10353062). [PMID](/source/PMID_(identifier)) [37470013](https://pubmed.ncbi.nlm.nih.gov/37470013).

1. **[^](#cite_ref-FDA_levmetamfetamine_32-0)** ["Code of Federal Regulations Title 21: Subchapter D – Drugs for human use, Part 341 – cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use"](https://web.archive.org/web/20191225081836/https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=341.80). *United States Food and Drug Administration*. April 2015. Archived from [the original](https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=341.80) on 25 December 2019. Retrieved 7 March 2016. Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in every 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.

1. **[^](#cite_ref-33)** ["Levomethamphetamine: Identification"](https://pubchem.ncbi.nlm.nih.gov/compound/36604). *Pubchem Compound*. National Center for Biotechnology Information. [Archived](https://web.archive.org/web/20141006215922/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=36604#section=Identification) from the original on 6 October 2014. Retrieved 4 September 2017.

1. ^ [***a***](#cite_ref-Hart_2011_35-0) [***b***](#cite_ref-Hart_2011_35-1) Hart CL, Marvin CB, Silver R, Smith EE (February 2012). ["Is cognitive functioning impaired in methamphetamine users? A critical review"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260986). *Neuropsychopharmacology*. **37** (3): 586–608. [doi](/source/Doi_(identifier)):[10.1038/npp.2011.276](https://doi.org/10.1038%2Fnpp.2011.276). [PMC](/source/PMC_(identifier)) [3260986](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260986). [PMID](/source/PMID_(identifier)) [22089317](https://pubmed.ncbi.nlm.nih.gov/22089317). There are several amphetamines used recreationally, including d-amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine, and 3,4-methylenedioxymethamphetamine. Of these compounds, methamphetamine has generated the greatest amount of concern. Indeed, periodically there are statements in the scientific and popular literature attesting to methamphetamine's greater potency and 'addictive' potential, relative to other amphetamines. Such statements, however, are inconsistent with data collected in humans, which show that d-amphetamine and methamphetamine produce nearly identical physiological and behavioral effects (eg, Martin et al, 1971; Sevak et al, 2009; Kirkpatrick et al, in press a).

1. **[^](#cite_ref-AP-NBC_2004_36-0)** ["Meth's aphrodisiac effect adds to drug's allure"](https://web.archive.org/web/20130812083225/http://www.nbcnews.com/id/6646180/ns/health-addictions/t/meths-aphrodisiac-effect-adds-drugs-allure/). *NBC News*. Associated Press. 3 December 2004. Archived from [the original](http://www.nbcnews.com/id/6646180/ns/health-addictions/t/meths-aphrodisiac-effect-adds-drugs-allure/) on 12 August 2013. Retrieved 12 September 2019.

1. ^ [***a***](#cite_ref-pmid25861156_37-0) [***b***](#cite_ref-pmid25861156_37-1) [***c***](#cite_ref-pmid25861156_37-2) Yu S, Zhu L, Shen Q, Bai X, Di X (March 2015). ["Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377385). *Behavioural Neurology*. **2015** (103969): 1–11. [doi](/source/Doi_(identifier)):[10.1155/2015/103969](https://doi.org/10.1155%2F2015%2F103969). [PMC](/source/PMC_(identifier)) [4377385](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377385). [PMID](/source/PMID_(identifier)) [25861156](https://pubmed.ncbi.nlm.nih.gov/25861156).

1. ^ [***a***](#cite_ref-pmid19328213_38-0) [***b***](#cite_ref-pmid19328213_38-1) [***c***](#cite_ref-pmid19328213_38-2) [***d***](#cite_ref-pmid19328213_38-3) [***e***](#cite_ref-pmid19328213_38-4) [***f***](#cite_ref-pmid19328213_38-5) [***g***](#cite_ref-pmid19328213_38-6) [***h***](#cite_ref-pmid19328213_38-7) Krasnova IN, Cadet JL (May 2009). ["Methamphetamine toxicity and messengers of death"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235). *Brain Res. Rev*. **60** (2): 379–407. [doi](/source/Doi_(identifier)):[10.1016/j.brainresrev.2009.03.002](https://doi.org/10.1016%2Fj.brainresrev.2009.03.002). [PMC](/source/PMC_(identifier)) [2731235](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731235). [PMID](/source/PMID_(identifier)) [19328213](https://pubmed.ncbi.nlm.nih.gov/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).

1. ^ [***a***](#cite_ref-pmid22089317_39-0) [***b***](#cite_ref-pmid22089317_39-1) Hart CL, Marvin CB, Silver R, Smith EE (February 2012). ["Is cognitive functioning impaired in methamphetamine users? A critical review"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260986). *Neuropsychopharmacology*. **37** (3): 586–608. [doi](/source/Doi_(identifier)):[10.1038/npp.2011.276](https://doi.org/10.1038%2Fnpp.2011.276). [PMC](/source/PMC_(identifier)) [3260986](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260986). [PMID](/source/PMID_(identifier)) [22089317](https://pubmed.ncbi.nlm.nih.gov/22089317).

1. **[^](#cite_ref-pmid8341891_40-0)** Mitler MM, Hajdukovic R, Erman MK (1993). ["Treatment of narcolepsy with methamphetamine"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2267865). *Sleep*. **16** (4): 306–317. [PMC](/source/PMC_(identifier)) [2267865](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2267865). [PMID](/source/PMID_(identifier)) [8341891](https://pubmed.ncbi.nlm.nih.gov/8341891).

1. **[^](#cite_ref-41)** Morgenthaler TI, Kapur VK, Brown T, Swick TJ, Alessi C, Aurora RN, et al. (2007). ["Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2276123). *Sleep*. **30** (12): 1705–11. [doi](/source/Doi_(identifier)):[10.1093/sleep/30.12.1705](https://doi.org/10.1093%2Fsleep%2F30.12.1705). [PMC](/source/PMC_(identifier)) [2276123](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2276123). [PMID](/source/PMID_(identifier)) [18246980](https://pubmed.ncbi.nlm.nih.gov/18246980).

1. **[^](#cite_ref-methamfetamine_INN_42-0)** Yoshida T (1997). ["Chapter 1: Use and Misuse of Amphetamines: An International Overview"](https://books.google.com/books?id=gVw_wzZU4x8C&pg=PA2). In Klee H (ed.). [*Amphetamine Misuse: International Perspectives on Current Trends*](https://archive.org/details/amphetaminemisus0000unse/page/2). Amsterdam, Netherlands: Harwood Academic Publishers. p. [2](https://archive.org/details/amphetaminemisus0000unse/page/2). [ISBN](/source/ISBN_(identifier)) [978-90-5702-081-0](https://en.wikipedia.org/wiki/Special:BookSources/978-90-5702-081-0). Methamphetamine (INN: metamfetamine) is the N-methyl derivative of amphetamine. Unlike amfetamine (INN) which corresponds to the racemic mixture, metamfetamine (INN) refers to the dextro-isomer of l-phenyl-2-methylaminopropane.

1. **[^](#cite_ref-Adderall_IR_43-0)** ["Adderall- dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate tablet"](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f22635fe-821d-4cde-aa12-419f8b53db81). *DailyMed*. Teva Pharmaceuticals USA, Inc. 29 May 2024. Retrieved 3 December 2024.

1. **[^](#cite_ref-Dextroamphetamine_FDA_label_44-0)** ["Dextroamphetamine sulfate tablet"](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e05cf690-d45a-4696-a1bf-40c9350cc084). *DailyMed*. 10 July 2023. Retrieved 3 December 2024.

1. **[^](#cite_ref-45)** ["Desoxyn Gradumet Side Effects"](https://www.drugs.com/sfx/desoxyn-gradumet-side-effects.html). *Drugs.com*. 19 March 2022. [Archived](https://web.archive.org/web/20221018043550/https://www.drugs.com/sfx/desoxyn-gradumet-side-effects.html) from the original on 18 October 2022. Retrieved 18 October 2022.

1. ^ [***a***](#cite_ref-SF_Meth_46-0) [***b***](#cite_ref-SF_Meth_46-1) [***c***](#cite_ref-SF_Meth_46-2) [***d***](#cite_ref-SF_Meth_46-3) [***e***](#cite_ref-SF_Meth_46-4) [***f***](#cite_ref-SF_Meth_46-5) [*San Francisco Meth Zombies*](https://web.archive.org/web/20160708142916/http://channel.nationalgeographic.com/drugs-inc/episodes/san-francisco-meth-zombies/) (TV documentary). National Geographic Channel. August 2013. [ASIN](/source/ASIN_(identifier)) [B00EHAOBAO](https://www.amazon.com/dp/B00EHAOBAO). Archived from [the original](http://channel.nationalgeographic.com/drugs-inc/episodes/san-francisco-meth-zombies/) on 8 July 2016. Retrieved 7 July 2016.

1. **[^](#cite_ref-47)** Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE (2011). *Goldfrank's toxicologic emergencies* (9th ed.). New York: McGraw-Hill Medical. p. 1080. [ISBN](/source/ISBN_(identifier)) [978-0-07-160593-9](https://en.wikipedia.org/wiki/Special:BookSources/978-0-07-160593-9).

1. **[^](#cite_ref-48)** Nutt DJ, King LA, Phillips LD (November 2010). "Drug harms in the UK: a multicriteria decision analysis". *Lancet*. **376** (9752): 1558–1565. [Bibcode](/source/Bibcode_(identifier)):[2010Lanc..376.1558N](https://ui.adsabs.harvard.edu/abs/2010Lanc..376.1558N). [doi](/source/Doi_(identifier)):[10.1016/S0140-6736(10)61462-6](https://doi.org/10.1016%2FS0140-6736%2810%2961462-6). [PMID](/source/PMID_(identifier)) [21036393](https://pubmed.ncbi.nlm.nih.gov/21036393).

1. **[^](#cite_ref-l781_49-0)** Rolles S, Measham F (July 2011). "Questioning the method and utility of ranking drug harms in drug policy". *The International Journal on Drug Policy*. **22** (4): 243–246. [doi](/source/Doi_(identifier)):[10.1016/j.drugpo.2011.04.004](https://doi.org/10.1016%2Fj.drugpo.2011.04.004). [PMID](/source/PMID_(identifier)) [21652195](https://pubmed.ncbi.nlm.nih.gov/21652195).

1. **[^](#cite_ref-w393_50-0)** Caulkins JP, Reuter P, Coulson C (November 2011). "Basing drug scheduling decisions on scientific ranking of harmfulness: false promise from false premises". *Addiction*. **106** (11): 1886–1890. [doi](/source/Doi_(identifier)):[10.1111/j.1360-0443.2011.03461.x](https://doi.org/10.1111%2Fj.1360-0443.2011.03461.x). [PMID](/source/PMID_(identifier)) [21895823](https://pubmed.ncbi.nlm.nih.gov/21895823).

1. **[^](#cite_ref-51)** Kevil CG, Goeders NE, Woolard MD, Bhuiyan MS, Dominic P, Kolluru GK, et al. (September 2019). ["Methamphetamine Use and Cardiovascular Disease"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709697). *Arteriosclerosis, Thrombosis, and Vascular Biology*. **39** (9): 1739–1746. [doi](/source/Doi_(identifier)):[10.1161/ATVBAHA.119.312461](https://doi.org/10.1161%2FATVBAHA.119.312461). [PMC](/source/PMC_(identifier)) [6709697](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709697). [PMID](/source/PMID_(identifier)) [31433698](https://pubmed.ncbi.nlm.nih.gov/31433698).

1. ^ [***a***](#cite_ref-Westfall_52-0) [***b***](#cite_ref-Westfall_52-1) [***c***](#cite_ref-Westfall_52-2) [***d***](#cite_ref-Westfall_52-3) Westfall DP, Westfall TC (2010). ["Miscellaneous Sympathomimetic Agonists"](https://web.archive.org/web/20131110094145/http://www.accessmedicine.com/content.aspx?aID=16661601). In Brunton LL, Chabner BA, Knollmann BC (eds.). *Goodman & Gilman's Pharmacological Basis of Therapeutics* (12th ed.). New York: McGraw-Hill. [ISBN](/source/ISBN_(identifier)) [978-0-07-162442-8](https://en.wikipedia.org/wiki/Special:BookSources/978-0-07-162442-8). Archived from [the original](http://www.accessmedicine.com/content.aspx?aID=16661601) on 10 November 2013. Retrieved 1 January 2014.

1. ^ [***a***](#cite_ref-NIH-What_53-0) [***b***](#cite_ref-NIH-What_53-1) ["What are the long-term effects of methamphetamine misuse?"](https://www.drugabuse.gov/publications/research-reports/methamphetamine/what-are-long-term-effects-methamphetamine-misuse). *National Institute on Drug Abuse*. [National Institutes of Health](/source/National_Institutes_of_Health), U.S. Department of Health & Human Services. October 2019. [Archived](https://web.archive.org/web/20200329012502/https://www.drugabuse.gov/publications/research-reports/methamphetamine/what-are-long-term-effects-methamphetamine-misuse) from the original on 29 March 2020. Retrieved 15 March 2020.

1. ^ [***a***](#cite_ref-Elkins_54-0) [***b***](#cite_ref-Elkins_54-1) Elkins C (27 February 2020). ["Meth Sores"](https://www.drugrehab.com/addiction/drugs/crystal-meth/sores/). *DrugRehab.com*. Advanced Recovery Systems. [Archived](https://web.archive.org/web/20200814113224/https://www.drugrehab.com/addiction/drugs/crystal-meth/sores/) from the original on 14 August 2020. Retrieved 15 March 2020.

1. **[^](#cite_ref-55)** National Institute on Drug Abuse (29 January 2021). ["Overdose Death Rates"](https://www.drugabuse.gov/drug-topics/trends-statistics/overdose-death-rates). *National Institute on Drug Abuse*. [Archived](https://web.archive.org/web/20180125182059/https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates) from the original on 25 January 2018. Retrieved 8 October 2020.

1. ^ [***a***](#cite_ref-ScienceDaily_56-0) [***b***](#cite_ref-ScienceDaily_56-1) ["Accelerated cellular aging caused by methamphetamine use limited in lab"](https://www.sciencedaily.com/releases/2015/02/150211153838.htm). *ScienceDaily*. 11 February 2015. [Archived](https://web.archive.org/web/20240922021108/https://www.sciencedaily.com/releases/2015/02/150211153838.htm) from the original on 22 September 2024. Retrieved 29 July 2024.

1. ^ [***a***](#cite_ref-pmid22782046_57-0) [***b***](#cite_ref-pmid22782046_57-1) [***c***](#cite_ref-pmid22782046_57-2) Hussain F, Frare RW, Py Berrios KL (2012). "Drug abuse identification and pain management in dental patients: a case study and literature review". *Gen. Dent*. **60** (4): 334–345. [PMID](/source/PMID_(identifier)) [22782046](https://pubmed.ncbi.nlm.nih.gov/22782046).

1. **[^](#cite_ref-ADA_58-0)** ["Methamphetamine Use (Meth Mouth)"](https://web.archive.org/web/20080601035323/http://www.ada.org/prof/resources/topics/methmouth.asp). American Dental Association. Archived from [the original](http://www.ada.org/prof/resources/topics/methmouth.asp) on 1 June 2008. Retrieved 15 December 2006.

1. ^ [***a***](#cite_ref-STD_59-0) [***b***](#cite_ref-STD_59-1) Halkitis PN, Pandey Mukherjee P, Palamar JJ (2008). ["Longitudinal Modeling of Methamphetamine Use and Sexual Risk Behaviors in Gay and Bisexual Men"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669892). *AIDS and Behavior*. **13** (4): 783–791. [doi](/source/Doi_(identifier)):[10.1007/s10461-008-9432-y](https://doi.org/10.1007%2Fs10461-008-9432-y). [PMC](/source/PMC_(identifier)) [4669892](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669892). [PMID](/source/PMID_(identifier)) [18661225](https://pubmed.ncbi.nlm.nih.gov/18661225).

1. ^ [***a***](#cite_ref-Patrick_Moore_60-0) [***b***](#cite_ref-Patrick_Moore_60-1) Moore P (June 2005). ["We Are Not OK"](https://web.archive.org/web/20110604154056/http://www.villagevoice.com/2005-06-14/people/we-are-not-ok/). VillageVoice. Archived from [the original](http://www.villagevoice.com/2005-06-14/people/we-are-not-ok/) on 4 June 2011. Retrieved 15 January 2011.

1. ^ [***a***](#cite_ref-unsw_61-0) [***b***](#cite_ref-unsw_61-1) ["Methamphetamine Use and Health | UNSW: The University of New South Wales – Faculty of Medicine"](https://web.archive.org/web/20080816134234/http://www.med.unsw.edu.au/NDARCWeb.nsf/resources/NDLERF_Methamphetamine/%24file/NDLERF%2BUSE%2BAND%2BHEALTH.pdf) (PDF). Archived from [the original](http://www.med.unsw.edu.au/NDARCWeb.nsf/resources/NDLERF_Methamphetamine/$file/NDLERF+USE+AND+HEALTH.pdf) (PDF) on 16 August 2008. Retrieved 15 January 2011.

1. ^ [***a***](#cite_ref-Merck_Manual_Amphetamines_62-0) [***b***](#cite_ref-Merck_Manual_Amphetamines_62-1) O'Connor PG (February 2012). ["Amphetamines"](http://www.merckmanuals.com/professional/special_subjects/drug_use_and_dependence/amphetamines.html). *Merck Manual for Health Care Professionals*. Merck. [Archived](https://web.archive.org/web/20120506232123/http://www.merckmanuals.com/professional/special_subjects/drug_use_and_dependence/amphetamines.html) from the original on 6 May 2012. Retrieved 8 May 2012.

1. **[^](#cite_ref-NeurClin_63-0)** Rusinyak DE (2011). ["Neurologic manifestations of chronic methamphetamine abuse"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148451). *Neurologic Clinics*. **29** (3): 641–655. [doi](/source/Doi_(identifier)):[10.1016/j.ncl.2011.05.004](https://doi.org/10.1016%2Fj.ncl.2011.05.004). [PMC](/source/PMC_(identifier)) [3148451](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148451). [PMID](/source/PMID_(identifier)) [21803215](https://pubmed.ncbi.nlm.nih.gov/21803215).

1. **[^](#cite_ref-Darke-2008_64-0)** Darke S, Kaye S, McKetin R, Duflou J (May 2008). "Major physical and psychological harms of methamphetamine use". *Drug Alcohol Rev*. **27** (3): 253–262. [doi](/source/Doi_(identifier)):[10.1080/09595230801923702](https://doi.org/10.1080%2F09595230801923702). [PMID](/source/PMID_(identifier)) [18368606](https://pubmed.ncbi.nlm.nih.gov/18368606).

1. **[^](#cite_ref-Sword_65-0)** Raskin S (26 December 2021). ["Missouri sword slay suspect smiles for mug shot after allegedly killing beau"](https://nypost.com/2021/12/26/missouri-woman-grins-for-mug-shot-after-alleged-sword-slay/). New York Post. [Archived](https://web.archive.org/web/20211226192534/https://nypost.com/2021/12/26/missouri-woman-grins-for-mug-shot-after-alleged-sword-slay/) from the original on 26 December 2021. Retrieved 26 December 2021.

1. ^ [***a***](#cite_ref-Glial_tox_review_–_Ntox_diagram_66-0) [***b***](#cite_ref-Glial_tox_review_–_Ntox_diagram_66-1) Beardsley PM, Hauser KF (2014). "Glial Modulators as Potential Treatments of Psychostimulant Abuse". *Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse*. Advances in Pharmacology. Vol. 69. Academic Press. pp. 1–69. [doi](/source/Doi_(identifier)):[10.1016/B978-0-12-420118-7.00001-9](https://doi.org/10.1016%2FB978-0-12-420118-7.00001-9). [ISBN](/source/ISBN_(identifier)) [978-0-12-420118-7](https://en.wikipedia.org/wiki/Special:BookSources/978-0-12-420118-7). [PMC](/source/PMC_(identifier)) [4103010](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103010). [PMID](/source/PMID_(identifier)) [24484974](https://pubmed.ncbi.nlm.nih.gov/24484974). Glia (including astrocytes, microglia, and oligodendrocytes), which constitute the majority of cells in the brain, have many of the same receptors as neurons, secrete neurotransmitters and neurotrophic and neuroinflammatory factors, control clearance of neurotransmitters from synaptic clefts, and are intimately involved in synaptic plasticity. Despite their prevalence and spectrum of functions, appreciation of their potential general importance has been elusive since their identification in the mid-1800s, and only relatively recently have they been gaining their due respect. This development of appreciation has been nurtured by the growing awareness that drugs of abuse, including the psychostimulants, affect glial activity, and glial activity, in turn, has been found to modulate the effects of the psychostimulants

1. **[^](#cite_ref-Neuroimmune_meth_toxicity_67-0)** >See Fig. 7.1 in Loftis JM, Janowsky A (2014). "Neuroimmune basis of methamphetamine toxicity". *Neuroimmune Signaling in Drug Actions and Addictions*. International Review of Neurobiology. Vol. 118. Academic Press. pp. 165–197. [doi](/source/Doi_(identifier)):[10.1016/B978-0-12-801284-0.00007-5](https://doi.org/10.1016%2FB978-0-12-801284-0.00007-5). [ISBN](/source/ISBN_(identifier)) [978-0-12-801284-0](https://en.wikipedia.org/wiki/Special:BookSources/978-0-12-801284-0). [PMC](/source/PMC_(identifier)) [4418472](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418472). [PMID](/source/PMID_(identifier)) [25175865](https://pubmed.ncbi.nlm.nih.gov/25175865). Collectively, these pathological processes contribute to neurotoxicity (e.g., increased BBB permeability, inflammation, neuronal degeneration, cell death) and neuropsychiatric impairments (e.g., cognitive eficits, mood disorders)

1. ^ [***a***](#cite_ref-Sigma_68-0) [***b***](#cite_ref-Sigma_68-1) [***c***](#cite_ref-Sigma_68-2) [***d***](#cite_ref-Sigma_68-3) [***e***](#cite_ref-Sigma_68-4) Kaushal N, Matsumoto RR (March 2011). ["Role of sigma receptors in methamphetamine-induced neurotoxicity"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137201). *Curr Neuropharmacol*. **9** (1): 54–57. [doi](/source/Doi_(identifier)):[10.2174/157015911795016930](https://doi.org/10.2174%2F157015911795016930). [PMC](/source/PMC_(identifier)) [3137201](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137201). [PMID](/source/PMID_(identifier)) [21886562](https://pubmed.ncbi.nlm.nih.gov/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].

1. **[^](#cite_ref-pmid22392347_69-0)** Carvalho M, Carmo H, Costa VM, Capela JP, Pontes H, Remião F, et al. (August 2012). "Toxicity of amphetamines: an update". *Arch. Toxicol*. **86** (8): 1167–1231. [Bibcode](/source/Bibcode_(identifier)):[2012ArTox..86.1167C](https://ui.adsabs.harvard.edu/abs/2012ArTox..86.1167C). [doi](/source/Doi_(identifier)):[10.1007/s00204-012-0815-5](https://doi.org/10.1007%2Fs00204-012-0815-5). [PMID](/source/PMID_(identifier)) [22392347](https://pubmed.ncbi.nlm.nih.gov/22392347).

1. ^ [***a***](#cite_ref-Cisneros_2014_and_review_70-0) [***b***](#cite_ref-Cisneros_2014_and_review_70-1) [***c***](#cite_ref-Cisneros_2014_and_review_70-2) [***d***](#cite_ref-Cisneros_2014_and_review_70-3) • Cisneros IE, Ghorpade A (October 2014). ["Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315503). *Neuropharmacology*. **85**: 499–507. [doi](/source/Doi_(identifier)):[10.1016/j.neuropharm.2014.06.011](https://doi.org/10.1016%2Fj.neuropharm.2014.06.011). [PMC](/source/PMC_(identifier)) [4315503](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315503). [PMID](/source/PMID_(identifier)) [24950453](https://pubmed.ncbi.nlm.nih.gov/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"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532615). *Eur. J. Pharmacol*. **761**: 345–352. [doi](/source/Doi_(identifier)):[10.1016/j.ejphar.2015.06.019](https://doi.org/10.1016%2Fj.ejphar.2015.06.019). [PMC](/source/PMC_(identifier)) [4532615](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4532615). [PMID](/source/PMID_(identifier)) [26092759](https://pubmed.ncbi.nlm.nih.gov/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)

1. **[^](#cite_ref-71)** 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](/source/Doi_(identifier)):[10.1124/jpet.105.096503](https://doi.org/10.1124%2Fjpet.105.096503). [PMID](/source/PMID_(identifier)) [16293712](https://pubmed.ncbi.nlm.nih.gov/16293712).

1. ^ [***a***](#cite_ref-SigmaB_72-0) [***b***](#cite_ref-SigmaB_72-1) [***c***](#cite_ref-SigmaB_72-2) [***d***](#cite_ref-SigmaB_72-3) 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](/source/Doi_(identifier)):[10.2174/1874473711003030156](https://doi.org/10.2174%2F1874473711003030156). [PMID](/source/PMID_(identifier)) [21054260](https://pubmed.ncbi.nlm.nih.gov/21054260).

1. **[^](#cite_ref-Addiction_glossary_73-0)** Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). *Molecular Neuropharmacology: A Foundation for Clinical Neuroscience* (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375. [ISBN](/source/ISBN_(identifier)) [9780071481274](https://en.wikipedia.org/wiki/Special:BookSources/9780071481274).

1. ^ [***a***](#cite_ref-Cellular_basis_74-0) [***b***](#cite_ref-Cellular_basis_74-1) [***c***](#cite_ref-Cellular_basis_74-2) [***d***](#cite_ref-Cellular_basis_74-3) Nestler EJ (December 2013). ["Cellular basis of memory for addiction"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681). *Dialogues in Clinical Neuroscience*. **15** (4): 431–443. [PMC](/source/PMC_(identifier)) [3898681](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3898681). [PMID](/source/PMID_(identifier)) [24459410](https://pubmed.ncbi.nlm.nih.gov/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.

1. **[^](#cite_ref-Brain_disease_75-0)** Volkow ND, Koob GF, McLellan AT (January 2016). ["Neurobiologic Advances from the Brain Disease Model of Addiction"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135257). *New England Journal of Medicine*. **374** (4): 363–371. [doi](/source/Doi_(identifier)):[10.1056/NEJMra1511480](https://doi.org/10.1056%2FNEJMra1511480). [PMC](/source/PMC_(identifier)) [6135257](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135257). [PMID](/source/PMID_(identifier)) [26816013](https://pubmed.ncbi.nlm.nih.gov/26816013). Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe. Addiction: A term used to indicate the most severe, chronic stage of substance-use disorder, in which there is a substantial loss of self-control, as indicated by compulsive drug taking despite the desire to stop taking the drug. In the DSM-5, the term addiction is synonymous with the classification of severe substance-use disorder.

1. ^ [***a***](#cite_ref-Nestler-Renthal_Figure_2_77-0) [***b***](#cite_ref-Nestler-Renthal_Figure_2_77-1) [***c***](#cite_ref-Nestler-Renthal_Figure_2_77-2) Renthal W, Nestler EJ (September 2009). ["Chromatin regulation in drug addiction and depression"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834246). *Dialogues in Clinical Neuroscience*. **11** (3): 257–268. [doi](/source/Doi_(identifier)):[10.31887/DCNS.2009.11.3/wrenthal](https://doi.org/10.31887%2FDCNS.2009.11.3%2Fwrenthal). [PMC](/source/PMC_(identifier)) [2834246](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834246). [PMID](/source/PMID_(identifier)) [19877494](https://pubmed.ncbi.nlm.nih.gov/19877494). [Psychostimulants] increase cAMP levels in striatum, which activates protein kinase A (PKA) and leads to phosphorylation of its targets. This includes the cAMP response element binding protein (CREB), the phosphorylation of which induces its association with the histone acetyltransferase, CREB binding protein (CBP) to acetylate histones and facilitate gene activation. This is known to occur on many genes including fosB and c-fos in response to psychostimulant exposure. ΔFosB is also upregulated by chronic psychostimulant treatments, and is known to activate certain genes (eg, cdk5) and repress others (eg, c-fos) where it recruits HDAC1 as a corepressor. ... Chronic exposure to psychostimulants increases glutamatergic [signaling] from the prefrontal cortex to the NAc. Glutamatergic signaling elevates Ca2+ levels in NAc postsynaptic elements where it activates CaMK (calcium/calmodulin protein kinases) signaling, which, in addition to phosphorylating CREB, also phosphorylates HDAC5. [Figure 2: Psychostimulant-induced signaling events](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834246/figure/DialoguesClinNeurosci-11-257-g002/)

1. **[^](#cite_ref-Glutamate-dopamine_cotransmission_review_78-0)** Broussard JI (January 2012). ["Co-transmission of dopamine and glutamate"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250102). *The Journal of General Physiology*. **139** (1): 93–96. [doi](/source/Doi_(identifier)):[10.1085/jgp.201110659](https://doi.org/10.1085%2Fjgp.201110659). [PMC](/source/PMC_(identifier)) [3250102](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250102). [PMID](/source/PMID_(identifier)) [22200950](https://pubmed.ncbi.nlm.nih.gov/22200950). Coincident and convergent input often induces plasticity on a postsynaptic neuron. The NAc integrates processed information about the environment from basolateral amygdala, hippocampus, and prefrontal cortex (PFC), as well as projections from midbrain dopamine neurons. Previous studies have demonstrated how dopamine modulates this integrative process. For example, high frequency stimulation potentiates hippocampal inputs to the NAc while simultaneously depressing PFC synapses (Goto and Grace, 2005). The converse was also shown to be true; stimulation at PFC potentiates PFC–NAc synapses but depresses hippocampal–NAc synapses. In light of the new functional evidence of midbrain dopamine/glutamate co-transmission (references above), new experiments of NAc function will have to test whether midbrain glutamatergic inputs bias or filter either limbic or cortical inputs to guide goal-directed behavior.

1. **[^](#cite_ref-Amphetamine_KEGG_ΔFosB_79-0)** Kanehisa Laboratories (10 October 2014). ["Amphetamine – Homo sapiens (human)"](http://www.genome.jp/kegg-bin/show_pathway?hsa05031+2354). *KEGG Pathway*. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.

1. **[^](#cite_ref-Meth_cAMP/calcium-dependent_cascade_80-0)** Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). ["Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359351). *Molecular Neurobiology*. **51** (2): 696–717 ([Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359351/figure/Fig1/)). [doi](/source/Doi_(identifier)):[10.1007/s12035-014-8776-8](https://doi.org/10.1007%2Fs12035-014-8776-8). [PMC](/source/PMC_(identifier)) [4359351](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359351). [PMID](/source/PMID_(identifier)) [24939695](https://pubmed.ncbi.nlm.nih.gov/24939695).

1. ^ [***a***](#cite_ref-Nestler1_81-0) [***b***](#cite_ref-Nestler1_81-1) [***c***](#cite_ref-Nestler1_81-2) Robison AJ, Nestler EJ (November 2011). ["Transcriptional and epigenetic mechanisms of addiction"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277). *Nature Reviews Neuroscience*. **12** (11): 623–637. [doi](/source/Doi_(identifier)):[10.1038/nrn3111](https://doi.org/10.1038%2Fnrn3111). [PMC](/source/PMC_(identifier)) [3272277](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277). [PMID](/source/PMID_(identifier)) [21989194](https://pubmed.ncbi.nlm.nih.gov/21989194). ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression. [Figure 4: Epigenetic basis of drug regulation of gene expression](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277/figure/F4/)

1. ^ [***a***](#cite_ref-Nestler2_82-0) [***b***](#cite_ref-Nestler2_82-1) [***c***](#cite_ref-Nestler2_82-2) Nestler EJ (December 2012). ["Transcriptional mechanisms of drug addiction"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569166). *Clinical Psychopharmacology and Neuroscience*. **10** (3): 136–143. [doi](/source/Doi_(identifier)):[10.9758/cpn.2012.10.3.136](https://doi.org/10.9758%2Fcpn.2012.10.3.136). [PMC](/source/PMC_(identifier)) [3569166](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569166). [PMID](/source/PMID_(identifier)) [23430970](https://pubmed.ncbi.nlm.nih.gov/23430970). The 35-37 kD ΔFosB isoforms accumulate with chronic drug exposure due to their extraordinarily long half-lives. ... As a result of its stability, the ΔFosB protein persists in neurons for at least several weeks after cessation of drug exposure. ... ΔFosB overexpression in nucleus accumbens induces NFκB ... In contrast, the ability of ΔFosB to repress the c-Fos gene occurs in concert with the recruitment of a histone deacetylase and presumably several other repressive proteins such as a repressive histone methyltransferase

1. **[^](#cite_ref-c-Fos_repression_83-0)** Nestler EJ (October 2008). ["Transcriptional mechanisms of addiction: Role of ΔFosB"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320). *Philosophical Transactions of the Royal Society B: Biological Sciences*. **363** (1507): 3245–3255. [doi](/source/Doi_(identifier)):[10.1098/rstb.2008.0067](https://doi.org/10.1098%2Frstb.2008.0067). [PMC](/source/PMC_(identifier)) [2607320](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2607320). [PMID](/source/PMID_(identifier)) [18640924](https://pubmed.ncbi.nlm.nih.gov/18640924). Recent evidence has shown that ΔFosB also represses the c-fos gene that helps create the molecular switch—from the induction of several short-lived Fos family proteins after acute drug exposure to the predominant accumulation of ΔFosB after chronic drug exposure

1. **[^](#cite_ref-Nestler,_Hyman,_and_Malenka_2_84-0)** Hyman SE, Malenka RC, Nestler EJ (July 2006). "Neural mechanisms of addiction: the role of reward-related learning and memory". *Annu. Rev. Neurosci*. **29**: 565–598. [doi](/source/Doi_(identifier)):[10.1146/annurev.neuro.29.051605.113009](https://doi.org/10.1146%2Fannurev.neuro.29.051605.113009). [PMID](/source/PMID_(identifier)) [16776597](https://pubmed.ncbi.nlm.nih.gov/16776597).

1. ^ [***a***](#cite_ref-Nestler_85-0) [***b***](#cite_ref-Nestler_85-1) [***c***](#cite_ref-Nestler_85-2) [***d***](#cite_ref-Nestler_85-3) [***e***](#cite_ref-Nestler_85-4) [***f***](#cite_ref-Nestler_85-5) [***g***](#cite_ref-Nestler_85-6) [***h***](#cite_ref-Nestler_85-7) Robison AJ, Nestler EJ (November 2011). ["Transcriptional and epigenetic mechanisms of addiction"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277). *Nat. Rev. Neurosci*. **12** (11): 623–637. [doi](/source/Doi_(identifier)):[10.1038/nrn3111](https://doi.org/10.1038%2Fnrn3111). [PMC](/source/PMC_(identifier)) [3272277](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272277). [PMID](/source/PMID_(identifier)) [21989194](https://pubmed.ncbi.nlm.nih.gov/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.

1. **[^](#cite_ref-NHM-Transcription_factor_86-0)** Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 4: Signal Transduction in the Brain". In Sydor A, Brown RY (eds.). *Molecular Neuropharmacology: A Foundation for Clinical Neuroscience* (2nd ed.). New York, USA: McGraw-Hill Medical. p. 94. [ISBN](/source/ISBN_(identifier)) [978-0-07-148127-4](https://en.wikipedia.org/wiki/Special:BookSources/978-0-07-148127-4).

1. ^ [***a***](#cite_ref-What_the_ΔFosB?_89-0) [***b***](#cite_ref-What_the_ΔFosB?_89-1) [***c***](#cite_ref-What_the_ΔFosB?_89-2) 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](/source/Doi_(identifier)):[10.3109/00952990.2014.933840](https://doi.org/10.3109%2F00952990.2014.933840). [PMID](/source/PMID_(identifier)) [25083822](https://pubmed.ncbi.nlm.nih.gov/25083822). ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.

1. ^ [***a***](#cite_ref-Natural_and_drug_addictions_90-0) [***b***](#cite_ref-Natural_and_drug_addictions_90-1) [***c***](#cite_ref-Natural_and_drug_addictions_90-2) [***d***](#cite_ref-Natural_and_drug_addictions_90-3) [***e***](#cite_ref-Natural_and_drug_addictions_90-4) [***f***](#cite_ref-Natural_and_drug_addictions_90-5) [***g***](#cite_ref-Natural_and_drug_addictions_90-6) [***h***](#cite_ref-Natural_and_drug_addictions_90-7) [***i***](#cite_ref-Natural_and_drug_addictions_90-8) [***j***](#cite_ref-Natural_and_drug_addictions_90-9) [***k***](#cite_ref-Natural_and_drug_addictions_90-10) [***l***](#cite_ref-Natural_and_drug_addictions_90-11) [***m***](#cite_ref-Natural_and_drug_addictions_90-12) [***n***](#cite_ref-Natural_and_drug_addictions_90-13) [***o***](#cite_ref-Natural_and_drug_addictions_90-14) [***p***](#cite_ref-Natural_and_drug_addictions_90-15) [***q***](#cite_ref-Natural_and_drug_addictions_90-16) [***r***](#cite_ref-Natural_and_drug_addictions_90-17) Olsen CM (December 2011). ["Natural rewards, neuroplasticity, and non-drug addictions"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704). *Neuropharmacology*. **61** (7): 1109–1122. [doi](/source/Doi_(identifier)):[10.1016/j.neuropharm.2011.03.010](https://doi.org/10.1016%2Fj.neuropharm.2011.03.010). [PMC](/source/PMC_(identifier)) [3139704](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139704). [PMID](/source/PMID_(identifier)) [21459101](https://pubmed.ncbi.nlm.nih.gov/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).

1. **[^](#cite_ref-Alcoholism_ΔFosB_91-0)** Kanehisa Laboratories (29 October 2014). ["Alcoholism – Homo sapiens (human)"](http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354). *KEGG Pathway*. [Archived](https://web.archive.org/web/20141013072800/http://www.genome.jp/kegg-bin/show_pathway?hsa05034+2354) from the original on 13 October 2014. Retrieved 31 October 2014.

1. **[^](#cite_ref-MPH_ΔFosB_92-0)** 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"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650365). *Proc. Natl. Acad. Sci. U.S.A*. **106** (8): 2915–2920. [Bibcode](/source/Bibcode_(identifier)):[2009PNAS..106.2915K](https://ui.adsabs.harvard.edu/abs/2009PNAS..106.2915K). [doi](/source/Doi_(identifier)):[10.1073/pnas.0813179106](https://doi.org/10.1073%2Fpnas.0813179106). [PMC](/source/PMC_(identifier)) [2650365](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650365). [PMID](/source/PMID_(identifier)) [19202072](https://pubmed.ncbi.nlm.nih.gov/19202072).

1. ^ [***a***](#cite_ref-pmid23643695_93-0) [***b***](#cite_ref-pmid23643695_93-1) Nestler EJ (January 2014). ["Epigenetic mechanisms of drug addiction"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384). *Neuropharmacology*. **76** (Pt B): 259–268. [doi](/source/Doi_(identifier)):[10.1016/j.neuropharm.2013.04.004](https://doi.org/10.1016%2Fj.neuropharm.2013.04.004). [PMC](/source/PMC_(identifier)) [3766384](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766384). [PMID](/source/PMID_(identifier)) [23643695](https://pubmed.ncbi.nlm.nih.gov/23643695).

1. ^ [***a***](#cite_ref-ΔFosB_reward_94-0) [***b***](#cite_ref-ΔFosB_reward_94-1) 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"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958). *Journal of Psychoactive Drugs*. **44** (1): 38–55. [doi](/source/Doi_(identifier)):[10.1080/02791072.2012.662112](https://doi.org/10.1080%2F02791072.2012.662112). [PMC](/source/PMC_(identifier)) [4040958](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4040958). [PMID](/source/PMID_(identifier)) [22641964](https://pubmed.ncbi.nlm.nih.gov/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.

1. ^ [***a***](#cite_ref-Amph_and_sex_addiction_96-0) [***b***](#cite_ref-Amph_and_sex_addiction_96-1) 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"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508). *J. Neurosci*. **33** (8): 3434–3442. [doi](/source/Doi_(identifier)):[10.1523/JNEUROSCI.4881-12.2013](https://doi.org/10.1523%2FJNEUROSCI.4881-12.2013). [PMC](/source/PMC_(identifier)) [3865508](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865508). [PMID](/source/PMID_(identifier)) [23426671](https://pubmed.ncbi.nlm.nih.gov/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

1. **[^](#cite_ref-pmid24685563_97-0)** Brecht ML, Herbeck D (June 2014). ["Time to relapse following treatment for methamphetamine use: a long-term perspective on patterns and predictors"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550209). *Drug Alcohol Depend*. **139**: 18–25. [doi](/source/Doi_(identifier)):[10.1016/j.drugalcdep.2014.02.702](https://doi.org/10.1016%2Fj.drugalcdep.2014.02.702). [PMC](/source/PMC_(identifier)) [4550209](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550209). [PMID](/source/PMID_(identifier)) [24685563](https://pubmed.ncbi.nlm.nih.gov/24685563).

1. **[^](#cite_ref-pmid23313146_98-0)** Brecht ML, Lovinger K, Herbeck DM, Urada D (2013). ["Patterns of treatment utilization and methamphetamine use during first 10 years after methamphetamine initiation"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602162). *J Subst Abuse Treat*. **44** (5): 548–56. [doi](/source/Doi_(identifier)):[10.1016/j.jsat.2012.12.006](https://doi.org/10.1016%2Fj.jsat.2012.12.006). [PMC](/source/PMC_(identifier)) [3602162](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3602162). [PMID](/source/PMID_(identifier)) [23313146](https://pubmed.ncbi.nlm.nih.gov/23313146).

1. ^ [***a***](#cite_ref-Godino_99-0) [***b***](#cite_ref-Godino_99-1) [***c***](#cite_ref-Godino_99-2) Godino A, Jayanthi S, Cadet JL (2015). ["Epigenetic landscape of amphetamine and methamphetamine addiction in rodents"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622560). *Epigenetics*. **10** (7): 574–80. [doi](/source/Doi_(identifier)):[10.1080/15592294.2015.1055441](https://doi.org/10.1080%2F15592294.2015.1055441). [PMC](/source/PMC_(identifier)) [4622560](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4622560). [PMID](/source/PMID_(identifier)) [26023847](https://pubmed.ncbi.nlm.nih.gov/26023847).

1. **[^](#cite_ref-pmid25446457_100-0)** Cruz FC, Javier Rubio F, Hope BT (December 2015). ["Using c-fos to study neuronal ensembles in corticostriatal circuitry of addiction"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427550). *Brain Res*. **1628** (Pt A): 157–73. [doi](/source/Doi_(identifier)):[10.1016/j.brainres.2014.11.005](https://doi.org/10.1016%2Fj.brainres.2014.11.005). [PMC](/source/PMC_(identifier)) [4427550](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4427550). [PMID](/source/PMID_(identifier)) [25446457](https://pubmed.ncbi.nlm.nih.gov/25446457).

1. **[^](#cite_ref-pmid24239129_101-0)** Jayanthi S, McCoy MT, Chen B, Britt JP, Kourrich S, Yau HJ, et al. (July 2014). ["Methamphetamine downregulates striatal glutamate receptors via diverse epigenetic mechanisms"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989474). *Biol. Psychiatry*. **76** (1): 47–56. [doi](/source/Doi_(identifier)):[10.1016/j.biopsych.2013.09.034](https://doi.org/10.1016%2Fj.biopsych.2013.09.034). [PMC](/source/PMC_(identifier)) [3989474](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989474). [PMID](/source/PMID_(identifier)) [24239129](https://pubmed.ncbi.nlm.nih.gov/24239129).

1. **[^](#cite_ref-pmid15120493_102-0)** Kenny PJ, Markou A (May 2004). "The ups and downs of addiction: role of metabotropic glutamate receptors". *Trends Pharmacol. Sci*. **25** (5): 265–72. [doi](/source/Doi_(identifier)):[10.1016/j.tips.2004.03.009](https://doi.org/10.1016%2Fj.tips.2004.03.009). [PMID](/source/PMID_(identifier)) [15120493](https://pubmed.ncbi.nlm.nih.gov/15120493).

1. **[^](#cite_ref-103)** Tokunaga I, Ishigami A, Kubo S, Gotohda T, Kitamura O (August 2008). ["The peroxidative DNA damage and apoptosis in methamphetamine-treated rat brain"](https://doi.org/10.2152%2Fjmi.55.241). *The Journal of Medical Investigation*. **55** (3–4): 241–245. [doi](/source/Doi_(identifier)):[10.2152/jmi.55.241](https://doi.org/10.2152%2Fjmi.55.241). [PMID](/source/PMID_(identifier)) [18797138](https://pubmed.ncbi.nlm.nih.gov/18797138).

1. **[^](#cite_ref-104)** Johnson Z, Venters J, Guarraci FA, Zewail-Foote M (June 2015). "Methamphetamine induces DNA damage in specific regions of the female rat brain". *Clinical and Experimental Pharmacology & Physiology*. **42** (6): 570–575. [doi](/source/Doi_(identifier)):[10.1111/1440-1681.12404](https://doi.org/10.1111%2F1440-1681.12404). [PMID](/source/PMID_(identifier)) [25867833](https://pubmed.ncbi.nlm.nih.gov/25867833).

1. **[^](#cite_ref-105)** Dabin J, Fortuny A, Polo SE (June 2016). ["Epigenome Maintenance in Response to DNA Damage"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476208). *Molecular Cell*. **62** (5): 712–727. [doi](/source/Doi_(identifier)):[10.1016/j.molcel.2016.04.006](https://doi.org/10.1016%2Fj.molcel.2016.04.006). [PMC](/source/PMC_(identifier)) [5476208](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5476208). [PMID](/source/PMID_(identifier)) [27259203](https://pubmed.ncbi.nlm.nih.gov/27259203).

1. ^ [***a***](#cite_ref-Psychosocial_interventions_network_meta-analysis_106-0) [***b***](#cite_ref-Psychosocial_interventions_network_meta-analysis_106-1) De Crescenzo F, Ciabattini M, D'Alò GL, De Giorgi R, Del Giovane C, Cassar C, et al. (December 2018). ["Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306153). *PLOS Medicine*. **15** (12) e1002715. [doi](/source/Doi_(identifier)):[10.1371/journal.pmed.1002715](https://doi.org/10.1371%2Fjournal.pmed.1002715). [PMC](/source/PMC_(identifier)) [6306153](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306153). [PMID](/source/PMID_(identifier)) [30586362](https://pubmed.ncbi.nlm.nih.gov/30586362).

1. **[^](#cite_ref-pmid24716825_107-0)** Stoops WW, Rush CR (May 2014). ["Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017926). *Expert Rev Clin Pharmacol*. **7** (3): 363–374. [doi](/source/Doi_(identifier)):[10.1586/17512433.2014.909283](https://doi.org/10.1586%2F17512433.2014.909283). [PMC](/source/PMC_(identifier)) [4017926](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017926). [PMID](/source/PMID_(identifier)) [24716825](https://pubmed.ncbi.nlm.nih.gov/24716825). Despite concerted efforts to identify a pharmacotherapy for managing stimulant use disorders, no widely effective medications have been approved.

1. ^ [***a***](#cite_ref-SystRev-Meta_analysis_amphetamine_addiction_pharmacotherapy_108-0) [***b***](#cite_ref-SystRev-Meta_analysis_amphetamine_addiction_pharmacotherapy_108-1) [***c***](#cite_ref-SystRev-Meta_analysis_amphetamine_addiction_pharmacotherapy_108-2) [***d***](#cite_ref-SystRev-Meta_analysis_amphetamine_addiction_pharmacotherapy_108-3) Chan B, Freeman M, Kondo K, Ayers C, Montgomery J, Paynter R, et al. (December 2019). "Pharmacotherapy for methamphetamine/amphetamine use disorder-a systematic review and meta-analysis". *Addiction*. **114** (12): 2122–2136. [doi](/source/Doi_(identifier)):[10.1111/add.14755](https://doi.org/10.1111%2Fadd.14755). [PMID](/source/PMID_(identifier)) [31328345](https://pubmed.ncbi.nlm.nih.gov/31328345).

1. **[^](#cite_ref-pmid23039267_109-0)** Forray A, Sofuoglu M (February 2014). ["Future pharmacological treatments for substance use disorders"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014020). *Br. J. Clin. Pharmacol*. **77** (2): 382–400. [doi](/source/Doi_(identifier)):[10.1111/j.1365-2125.2012.04474.x](https://doi.org/10.1111%2Fj.1365-2125.2012.04474.x). [PMC](/source/PMC_(identifier)) [4014020](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014020). [PMID](/source/PMID_(identifier)) [23039267](https://pubmed.ncbi.nlm.nih.gov/23039267).

1. **[^](#cite_ref-110)** ["Pharmacotherapy for methamphetamine/amphetamine use disorder—a systematic review and meta-analysis"](https://www.issup.net/files/2019-09/add.14755.pdf) (PDF). *issup.net*.

1. **[^](#cite_ref-111)** ["Crystal Meth Addiction"](https://redemptionrecoverygroup.com/addiction-recovery-resources/crystal-meth-addiction/). *Redemption Recovery*. Retrieved 22 March 2025.

1. **[^](#cite_ref-112)** O'Connor P. ["Amphetamines: Drug Use and Abuse"](https://web.archive.org/web/20070217053619/http://www.merck.com/mmhe/sec07/ch108/ch108g.html). *Merck Manual Home Health Handbook*. Merck. Archived from [the original](http://www.merckmanuals.com/home/special_subjects/drug_use_and_abuse/amphetamines.html) on 17 February 2007. Retrieved 27 February 2026.

1. **[^](#cite_ref-Cochrane_Abuse_113-0)** Pérez-Mañá C, Castells X, Torrens M, Capellà D, Farre M (2013). Pérez-Mañá C (ed.). ["Efficacy of psychostimulant drugs for amphetamine abuse or dependence"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521360). *Cochrane Database Syst. Rev*. **2013** (9) CD009695. [doi](/source/Doi_(identifier)):[10.1002/14651858.CD009695.pub2](https://doi.org/10.1002%2F14651858.CD009695.pub2). [PMC](/source/PMC_(identifier)) [11521360](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521360). [PMID](/source/PMID_(identifier)) [23996457](https://pubmed.ncbi.nlm.nih.gov/23996457).

1. ^ [***a***](#cite_ref-Cochrane_Withdrawal_114-0) [***b***](#cite_ref-Cochrane_Withdrawal_114-1) [***c***](#cite_ref-Cochrane_Withdrawal_114-2) [***d***](#cite_ref-Cochrane_Withdrawal_114-3) Shoptaw SJ, Kao U, Heinzerling K, Ling W (2009). Shoptaw SJ (ed.). ["Treatment for amphetamine withdrawal"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138250). *Cochrane Database Syst. Rev*. **2009** (2) CD003021. [doi](/source/Doi_(identifier)):[10.1002/14651858.CD003021.pub2](https://doi.org/10.1002%2F14651858.CD003021.pub2). [PMC](/source/PMC_(identifier)) [7138250](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138250). [PMID](/source/PMID_(identifier)) [19370579](https://pubmed.ncbi.nlm.nih.gov/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)

1. ^ [***a***](#cite_ref-pmid17990840_115-0) [***b***](#cite_ref-pmid17990840_115-1) [***c***](#cite_ref-pmid17990840_115-2) [***d***](#cite_ref-pmid17990840_115-3) Winslow BT, Voorhees KI, Pehl KA (2007). "Methamphetamine abuse". *American Family Physician*. **76** (8): 1169–1174. [PMID](/source/PMID_(identifier)) [17990840](https://pubmed.ncbi.nlm.nih.gov/17990840).

1. **[^](#cite_ref-2020-01-03_ABC_116-0)** Kennedy E (3 January 2020). ["Babies born to meth-affected mothers seem well behaved, but their passive nature masks a serious problem"](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). *[ABC News Online](/source/ABC_News_Online)*. Archived from [the original](https://www.abc.net.au/news/2020-01-03/the-hidden-problem-of-babies-born-to-meth-affected-mothers/11829668) on 24 October 2021.

1. **[^](#cite_ref-LaGasse_2012_117-0)** LaGasse LL, Derauf C, Smith LM, Newman E, Shah R, Neal C, et al. (April 2012). ["Prenatal methamphetamine exposure and childhood behavior problems at 3 and 5 years of age"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313637). *Pediatrics*. **129** (4). American Academy of Pediatrics: 681–8. [doi](/source/Doi_(identifier)):[10.1542/peds.2011-2209](https://doi.org/10.1542%2Fpeds.2011-2209). [PMC](/source/PMC_(identifier)) [3313637](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313637). [PMID](/source/PMID_(identifier)) [22430455](https://pubmed.ncbi.nlm.nih.gov/22430455).

1. **[^](#cite_ref-Albertson_2011_118-0)** Albertson TE (2011). "Amphetamines". In Olson KR, Anderson IB, Benowitz NL, Blanc PD, Kearney TE, Kim-Katz SY, Wu AH (eds.). *Poisoning & Drug Overdose* (6th ed.). New York: McGraw-Hill Medical. pp. 77–79. [ISBN](/source/ISBN_(identifier)) [978-0-07-166833-0](https://en.wikipedia.org/wiki/Special:BookSources/978-0-07-166833-0).

1. **[^](#cite_ref-119)** Oskie SM, Rhee JW (11 February 2011). ["Amphetamine Poisoning"](http://emergency.unboundmedicine.com/emergency/ub/view/5-Minute_Emergency_Consult/307063/all/Amphetamine_Poisoning). *Emergency Central*. Unbound Medicine. [Archived](https://web.archive.org/web/20130926150016/http://emergency.unboundmedicine.com/emergency/ub/view/5-Minute_Emergency_Consult/307063/all/Amphetamine_Poisoning) from the original on 26 September 2013. Retrieved 11 June 2013.

1. **[^](#cite_ref-pmid17874986_120-0)** Isbister GK, Buckley NA, Whyte IM (September 2007). "Serotonin toxicity: a practical approach to diagnosis and treatment". *Med. J. Aust*. **187** (6): 361–365. [doi](/source/Doi_(identifier)):[10.5694/j.1326-5377.2007.tb01282.x](https://doi.org/10.5694%2Fj.1326-5377.2007.tb01282.x). [PMID](/source/PMID_(identifier)) [17874986](https://pubmed.ncbi.nlm.nih.gov/17874986).

1. **[^](#cite_ref-Malenka_122-0)** Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). "Chapter 16: Reinforcement and Addictive Disorders". *Molecular Neuropharmacology: A Foundation for Clinical Neuroscience* (3rd ed.). New York: McGraw-Hill Medical. [ISBN](/source/ISBN_(identifier)) [978-0-07-182770-6](https://en.wikipedia.org/wiki/Special:BookSources/978-0-07-182770-6). Unlike cocaine and amphetamine, methamphetamine is directly toxic at higher doses to midbrain dopamine neurons

1. ^ [***a***](#cite_ref-Cochrane_123-0) [***b***](#cite_ref-Cochrane_123-1) [***c***](#cite_ref-Cochrane_123-2) Shoptaw SJ, Kao U, Ling W (2009). Shoptaw SJ, Ali R (eds.). ["Treatment for amphetamine psychosis"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004251). *Cochrane Database Syst. Rev*. **2009** (1) CD003026. [doi](/source/Doi_(identifier)):[10.1002/14651858.CD003026.pub3](https://doi.org/10.1002%2F14651858.CD003026.pub3). [PMC](/source/PMC_(identifier)) [7004251](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004251). [PMID](/source/PMID_(identifier)) [19160215](https://pubmed.ncbi.nlm.nih.gov/19160215). A minority of individuals who use amphetamines develop full-blown psychosis requiring care at emergency departments or psychiatric hospitals. In such cases, symptoms of amphetamine psychosis commonly include paranoid and persecutory delusions as well as auditory and visual hallucinations in the presence of extreme agitation. More common (about 18%) is for frequent amphetamine users to report psychotic symptoms that are sub-clinical and that do not require high-intensity intervention ... About 5–15% of the users who develop an amphetamine psychosis fail to recover completely (Hofmann 1983) ... Findings from one trial indicate use of antipsychotic medications effectively resolves symptoms of acute amphetamine psychosis.

1. **[^](#cite_ref-Hofmann_124-0)** Hofmann FG (1983). [*A Handbook on Drug and Alcohol Abuse: The Biomedical Aspects*](https://archive.org/details/handbookondrugal0002hofm/page/329) (2nd ed.). New York: Oxford University Press. p. [329](https://archive.org/details/handbookondrugal0002hofm/page/329). [ISBN](/source/ISBN_(identifier)) [978-0-19-503057-0](https://en.wikipedia.org/wiki/Special:BookSources/978-0-19-503057-0).

1. **[^](#cite_ref-Berman-2009_125-0)** Berman SM, Kuczenski R, McCracken JT, London ED (February 2009). ["Potential adverse effects of amphetamine treatment on brain and behavior: a review"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670101). *Mol. Psychiatry*. **14** (2): 123–142. [doi](/source/Doi_(identifier)):[10.1038/mp.2008.90](https://doi.org/10.1038%2Fmp.2008.90). [PMC](/source/PMC_(identifier)) [2670101](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670101). [PMID](/source/PMID_(identifier)) [18698321](https://pubmed.ncbi.nlm.nih.gov/18698321).

1. **[^](#cite_ref-126)** Spencer MR, Miniño AM, Warner M (December 2022). ["Drug Overdose Deaths in the United States, 2001–2021"](https://doi.org/10.15620%2Fcdc%3A122556). *NCHS Data Brief* (457). National Center for Health Statistics (U.S.): 1–8. [doi](/source/Doi_(identifier)):[10.15620/cdc:122556](https://doi.org/10.15620%2Fcdc%3A122556). [PMID](/source/PMID_(identifier)) [36598401](https://pubmed.ncbi.nlm.nih.gov/36598401).

1. **[^](#cite_ref-127)** Parish DC, Goyal H, Dane FC (May 2018). ["Mechanism of death: there's more to it than sudden cardiac arrest"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006107). *Journal of Thoracic Disease*. **10** (5): 3081–3087. [doi](/source/Doi_(identifier)):[10.21037/jtd.2018.04.113](https://doi.org/10.21037%2Fjtd.2018.04.113). [PMC](/source/PMC_(identifier)) [6006107](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006107). [PMID](/source/PMID_(identifier)) [29997977](https://pubmed.ncbi.nlm.nih.gov/29997977).

1. **[^](#cite_ref-128)** Noblett D, Hacein-Bey L, Waldau B, Ziegler J, Dahlin B, Chang J (February 2021). ["Increased rupture risk in small intracranial aneurysms associated with methamphetamine use"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903554). *Interventional Neuroradiology*. **27** (1): 75–80. [doi](/source/Doi_(identifier)):[10.1177/1591019920959534](https://doi.org/10.1177%2F1591019920959534). [PMC](/source/PMC_(identifier)) [7903554](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903554). [PMID](/source/PMID_(identifier)) [32967503](https://pubmed.ncbi.nlm.nih.gov/32967503).

1. **[^](#cite_ref-129)** Paone S, Clarkson L, Sin B, Punnapuzha S (August 2018). "Recognition of Sympathetic Crashing Acute Pulmonary Edema (SCAPE) and use of high-dose nitroglycerin infusion". *The American Journal of Emergency Medicine*. **36** (8): 1526.e5–1526.e7. [doi](/source/Doi_(identifier)):[10.1016/j.ajem.2018.05.013](https://doi.org/10.1016%2Fj.ajem.2018.05.013). [PMID](/source/PMID_(identifier)) [29776826](https://pubmed.ncbi.nlm.nih.gov/29776826).

1. **[^](#cite_ref-130)** Gholami F, Hosseini SH, Ahmadi A, Nabati M (15 October 2019). ["A Case report of hemodynamic instability, cardiac arrest, and acute severe dyspnea subsequent to inhalation of crystal methamphetamine"](https://doi.org/10.18502%2Fpbr.v5i2.1585). *Pharmaceutical and Biomedical Research*. [doi](/source/Doi_(identifier)):[10.18502/pbr.v5i2.1585](https://doi.org/10.18502%2Fpbr.v5i2.1585).

1. **[^](#cite_ref-131)** De Letter EA, Piette MH, Lambert WE, Cordonnier JA (January 2006). "Amphetamines as potential inducers of fatalities: a review in the district of Ghent from 1976-2004". *Medicine, Science, and the Law*. **46** (1): 37–65. [doi](/source/Doi_(identifier)):[10.1258/rsmmsl.46.1.37](https://doi.org/10.1258%2Frsmmsl.46.1.37). [PMID](/source/PMID_(identifier)) [16454462](https://pubmed.ncbi.nlm.nih.gov/16454462).

1. ^ [***a***](#cite_ref-Richards_2015_132-0) [***b***](#cite_ref-Richards_2015_132-1) [***c***](#cite_ref-Richards_2015_132-2) Richards JR, Albertson TE, Derlet RW, Lange RA, Olson KR, Horowitz BZ (May 2015). "Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review". *Drug Alcohol Depend*. **150**: 1–13. [doi](/source/Doi_(identifier)):[10.1016/j.drugalcdep.2015.01.040](https://doi.org/10.1016%2Fj.drugalcdep.2015.01.040). [PMID](/source/PMID_(identifier)) [25724076](https://pubmed.ncbi.nlm.nih.gov/25724076).

1. **[^](#cite_ref-133)** Richards JR, Derlet RW, Duncan DR (September 1997). "Methamphetamine toxicity: treatment with a benzodiazepine versus a butyrophenone". *Eur. J. Emerg. Med*. **4** (3): 130–135. [doi](/source/Doi_(identifier)):[10.1097/00063110-199709000-00003](https://doi.org/10.1097%2F00063110-199709000-00003). [PMID](/source/PMID_(identifier)) [9426992](https://pubmed.ncbi.nlm.nih.gov/9426992).

1. **[^](#cite_ref-Medscape_meth_toxicity_134-0)** Richards JR, Derlet RW, Albertson TE. ["Methamphetamine Toxicity: Treatment & Management"](http://emedicine.medscape.com/article/820918-treatment#showall). *Medscape*. WebMD. [Archived](https://web.archive.org/web/20160409114830/http://emedicine.medscape.com/article/820918-overview#showall) from the original on 9 April 2016. Retrieved 20 April 2016.

1. **[^](#cite_ref-135)** Farzam K, Jan A (2025), ["Beta Blockers"](https://www.ncbi.nlm.nih.gov/books/NBK532906/), *StatPearls*, Treasure Island (FL): StatPearls Publishing, [PMID](/source/PMID_(identifier)) [30422501](https://pubmed.ncbi.nlm.nih.gov/30422501), retrieved 22 March 2025

1. ^ [***a***](#cite_ref-DrugBank_Enzymes_136-0) [***b***](#cite_ref-DrugBank_Enzymes_136-1) ["Methamphetamine: Enzymes"](http://www.drugbank.ca/drugs/DB01577#enzymes). *DrugBank*. University of Alberta. 8 February 2013. [Archived](https://web.archive.org/web/20151228164940/http://www.drugbank.ca/drugs/DB01577#enzymes) from the original on 28 December 2015. Retrieved 2 January 2014.

1. **[^](#cite_ref-TreuerGauMéndez2013_137-0)** Treuer T, Gau SS, Méndez L, Montgomery W, Monk JA, Altin M, et al. (April 2013). ["A systematic review of combination therapy with stimulants and atomoxetine for attention-deficit/hyperactivity disorder, including patient characteristics, treatment strategies, effectiveness, and tolerability"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696926). *J Child Adolesc Psychopharmacol*. **23** (3): 179–193. [doi](/source/Doi_(identifier)):[10.1089/cap.2012.0093](https://doi.org/10.1089%2Fcap.2012.0093). [PMC](/source/PMC_(identifier)) [3696926](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696926). [PMID](/source/PMID_(identifier)) [23560600](https://pubmed.ncbi.nlm.nih.gov/23560600).

1. ^ [***a***](#cite_ref-HealSmithFindling2012_138-0) [***b***](#cite_ref-HealSmithFindling2012_138-1) Heal DJ, Smith SL, Findling RL (2012). "ADHD: current and future therapeutics". *Behavioral Neuroscience of Attention Deficit Hyperactivity Disorder and Its Treatment*. Current Topics in Behavioral Neurosciences. Vol. 9. pp. 361–390. [doi](/source/Doi_(identifier)):[10.1007/7854_2011_125](https://doi.org/10.1007%2F7854_2011_125). [ISBN](/source/ISBN_(identifier)) [978-3-642-24611-1](https://en.wikipedia.org/wiki/Special:BookSources/978-3-642-24611-1). [PMID](/source/PMID_(identifier)) [21487953](https://pubmed.ncbi.nlm.nih.gov/21487953). Adjunctive therapy with DL-methylphenidate in atomoxetine partial responders has been successful (Wilens et al. 2009), but this also increases the rates of insomnia, irritability and loss of appetite (Hammerness et al. 2009). This combination therapy has not included amphetamine because blockade of NET by atomoxetine prevents entry of amphetamine into presynaptic noradrenergic terminals (Sofuoglu et al. 2009).

1. **[^](#cite_ref-SofuogluPolingHill2009_139-0)** Sofuoglu M, Poling J, Hill K, Kosten T (2009). ["Atomoxetine attenuates dextroamphetamine effects in humans"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796580). *Am J Drug Alcohol Abuse*. **35** (6): 412–416. [doi](/source/Doi_(identifier)):[10.3109/00952990903383961](https://doi.org/10.3109%2F00952990903383961). [PMC](/source/PMC_(identifier)) [2796580](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796580). [PMID](/source/PMID_(identifier)) [20014909](https://pubmed.ncbi.nlm.nih.gov/20014909).

1. **[^](#cite_ref-ElkashefVocciHanson2008_140-0)** Elkashef A, Vocci F, Hanson G, White J, Wickes W, Tiihonen J (2008). ["Pharmacotherapy of methamphetamine addiction: an update"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597382). *Subst Abus*. **29** (3): 31–49. [Bibcode](/source/Bibcode_(identifier)):[2008JPkR...29...31E](https://ui.adsabs.harvard.edu/abs/2008JPkR...29...31E). [doi](/source/Doi_(identifier)):[10.1080/08897070802218554](https://doi.org/10.1080%2F08897070802218554). [PMC](/source/PMC_(identifier)) [2597382](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597382). [PMID](/source/PMID_(identifier)) [19042205](https://pubmed.ncbi.nlm.nih.gov/19042205).

1. **[^](#cite_ref-SimmlerWandelerLiechti2013_141-0)** Simmler LD, Wandeler R, Liechti ME (June 2013). ["Bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone antagonize methamphetamine-induced efflux of dopamine according to their potencies as dopamine uptake inhibitors: implications for the treatment of methamphetamine dependence"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679734). *BMC Res Notes*. **6** 220. [doi](/source/Doi_(identifier)):[10.1186/1756-0500-6-220](https://doi.org/10.1186%2F1756-0500-6-220). [PMC](/source/PMC_(identifier)) [3679734](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3679734). [PMID](/source/PMID_(identifier)) [23734766](https://pubmed.ncbi.nlm.nih.gov/23734766).

1. **[^](#cite_ref-NewtonRoacheDeLaGarza2006_142-0)** Newton TF, Roache JD, De La Garza R, Fong T, Wallace CL, Li SH, et al. (July 2006). "Bupropion reduces methamphetamine-induced subjective effects and cue-induced craving". *Neuropsychopharmacology*. **31** (7): 1537–1544. [doi](/source/Doi_(identifier)):[10.1038/sj.npp.1300979](https://doi.org/10.1038%2Fsj.npp.1300979). [PMID](/source/PMID_(identifier)) [16319910](https://pubmed.ncbi.nlm.nih.gov/16319910).

1. **[^](#cite_ref-ReithBLoughHong2015_143-0)** Reith ME, Blough BE, Hong WC, Jones KT, Schmitt KC, Baumann MH, et al. (February 2015). ["Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297708). *Drug and Alcohol Dependence*. **147**: 1–19. [doi](/source/Doi_(identifier)):[10.1016/j.drugalcdep.2014.12.005](https://doi.org/10.1016%2Fj.drugalcdep.2014.12.005). [PMC](/source/PMC_(identifier)) [4297708](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297708). [PMID](/source/PMID_(identifier)) [25548026](https://pubmed.ncbi.nlm.nih.gov/25548026).

1. ^ [***a***](#cite_ref-Forsyth2012_144-0) [***b***](#cite_ref-Forsyth2012_144-1) Forsyth AN (22 May 2012). ["Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines"](https://scholarworks.uno.edu/td/1436/). *ScholarWorks@UNO*. Retrieved 4 November 2024.

1. ^ [***a***](#cite_ref-Blough2008_145-0) [***b***](#cite_ref-Blough2008_145-1) Blough B (July 2008). ["Dopamine-releasing agents"](https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf) (PDF). In Trudell ML, Izenwasser S (eds.). [*Dopamine Transporters: Chemistry, Biology and Pharmacology*](https://books.google.com/books?id=QCagLAAACAAJ). Hoboken [NJ]: Wiley. pp. 305–320. [ISBN](/source/ISBN_(identifier)) [978-0-470-11790-3](https://en.wikipedia.org/wiki/Special:BookSources/978-0-470-11790-3). [OCLC](/source/OCLC_(identifier)) [181862653](https://search.worldcat.org/oclc/181862653). [OL](/source/OL_(identifier)) [18589888W](https://openlibrary.org/works/OL18589888W).

1. ^ [***a***](#cite_ref-RothmanBaumannDersch2001_146-0) [***b***](#cite_ref-RothmanBaumannDersch2001_146-1) [***c***](#cite_ref-RothmanBaumannDersch2001_146-2) Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll FI, et al. (January 2001). "Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin". *Synapse*. **39** (1): 32–41. [doi](/source/Doi_(identifier)):[10.1002/1098-2396(20010101)39:1<32::AID-SYN5>3.0.CO;2-3](https://doi.org/10.1002%2F1098-2396%2820010101%2939%3A1%3C32%3A%3AAID-SYN5%3E3.0.CO%3B2-3). [PMID](/source/PMID_(identifier)) [11071707](https://pubmed.ncbi.nlm.nih.gov/11071707).

1. **[^](#cite_ref-BaumannPartillaLehner2013_147-0)** Baumann MH, Partilla JS, Lehner KR, Thorndike EB, Hoffman AF, Holy M, et al. (2013). ["Powerful cocaine-like actions of 3,4-methylenedioxypyrovalerone (MDPV), a principal constituent of psychoactive 'bath salts' products"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572453). *Neuropsychopharmacology*. **38** (4): 552–562. [doi](/source/Doi_(identifier)):[10.1038/npp.2012.204](https://doi.org/10.1038%2Fnpp.2012.204). [PMC](/source/PMC_(identifier)) [3572453](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572453). [PMID](/source/PMID_(identifier)) [23072836](https://pubmed.ncbi.nlm.nih.gov/23072836).

1. **[^](#cite_ref-BaumannAyestasPartilla2012_148-0)** Baumann MH, Ayestas MA, Partilla JS, Sink JR, Shulgin AT, Daley PF, et al. (2012). ["The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306880). *Neuropsychopharmacology*. **37** (5): 1192–1203. [doi](/source/Doi_(identifier)):[10.1038/npp.2011.304](https://doi.org/10.1038%2Fnpp.2011.304). [PMC](/source/PMC_(identifier)) [3306880](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306880). [PMID](/source/PMID_(identifier)) [22169943](https://pubmed.ncbi.nlm.nih.gov/22169943).

1. **[^](#cite_ref-FitzgeraldGannonWalther2024_149-0)** Fitzgerald LR, Gannon BM, Walther D, Landavazo A, Hiranita T, Blough BE, et al. (March 2024). ["Structure-activity relationships for locomotor stimulant effects and monoamine transporter interactions of substituted amphetamines and cathinones"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10842458). *Neuropharmacology*. **245** 109827. [doi](/source/Doi_(identifier)):[10.1016/j.neuropharm.2023.109827](https://doi.org/10.1016%2Fj.neuropharm.2023.109827). [PMC](/source/PMC_(identifier)) [10842458](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10842458). [PMID](/source/PMID_(identifier)) [38154512](https://pubmed.ncbi.nlm.nih.gov/38154512). Although the number of amphetamine analogues with different amine substituents is relatively low in recreational drug markets (Cho and Segal, 1994), N-methyl and N-ethyl substitutions are sometimes found. Pharmacological activity of amphetamine-type drugs is decreased substantially if the N-alkyl chain is lengthened beyond ethyl, as previous studies show that N-propylamphetamine and N-butylamphetamine are ~4-fold and ~6-fold less potent than amphetamine in rats (Woolverton et al., 1980).

1. **[^](#cite_ref-Nicole2022_150-0)** Nicole L (2022). *In vivo Structure-Activity Relationships of Substituted Amphetamines and Substituted Cathinones* (Ph.D. thesis). University of Arkansas for Medical Sciences. [ProQuest](/source/ProQuest) [2711781450](https://www.proquest.com/docview/2711781450). FIGURE 2-6: Release: Effects of the specified test drug on monoamine release by DAT (red circles), NET (blue squares), and SERT (black triangles) in rat brain tissue. [...] EC50 values determined for the drug indicated within the panel. [...]

1. **[^](#cite_ref-RothmanBaumann2003_151-0)** Rothman RB, Baumann MH (October 2003). "Monoamine transporters and psychostimulant drugs". *Eur J Pharmacol*. **479** (1–3): 23–40. [doi](/source/Doi_(identifier)):[10.1016/j.ejphar.2003.08.054](https://doi.org/10.1016%2Fj.ejphar.2003.08.054). [PMID](/source/PMID_(identifier)) [14612135](https://pubmed.ncbi.nlm.nih.gov/14612135).

1. **[^](#cite_ref-RothmanBaumann2006_152-0)** Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". *Current Topics in Medicinal Chemistry*. **6** (17): 1845–1859. [doi](/source/Doi_(identifier)):[10.2174/156802606778249766](https://doi.org/10.2174%2F156802606778249766). [PMID](/source/PMID_(identifier)) [17017961](https://pubmed.ncbi.nlm.nih.gov/17017961).

1. ^ [***a***](#cite_ref-Miller_153-0) [***b***](#cite_ref-Miller_153-1) [***c***](#cite_ref-Miller_153-2) Miller GM (January 2011). ["The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005101). *J. Neurochem*. **116** (2): 164–176. [doi](/source/Doi_(identifier)):[10.1111/j.1471-4159.2010.07109.x](https://doi.org/10.1111%2Fj.1471-4159.2010.07109.x). [PMC](/source/PMC_(identifier)) [3005101](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005101). [PMID](/source/PMID_(identifier)) [21073468](https://pubmed.ncbi.nlm.nih.gov/21073468).

1. ^ [***a***](#cite_ref-Meth_Targets_154-0) [***b***](#cite_ref-Meth_Targets_154-1) [***c***](#cite_ref-Meth_Targets_154-2) ["Methamphetamine: Targets"](http://www.drugbank.ca/drugs/DB01577#targets). *DrugBank*. University of Alberta. 8 February 2013. [Archived](https://web.archive.org/web/20151228164940/http://www.drugbank.ca/drugs/DB01577#targets) from the original on 28 December 2015. Retrieved 4 January 2014.

1. **[^](#cite_ref-pmid11459929_155-0)** Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, et al. (July 2001). ["Trace amines: identification of a family of mammalian G protein-coupled receptors"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC55357). *Proc. Natl. Acad. Sci. U.S.A*. **98** (16): 8966–8971. [Bibcode](/source/Bibcode_(identifier)):[2001PNAS...98.8966B](https://ui.adsabs.harvard.edu/abs/2001PNAS...98.8966B). [doi](/source/Doi_(identifier)):[10.1073/pnas.151105198](https://doi.org/10.1073%2Fpnas.151105198). [PMC](/source/PMC_(identifier)) [55357](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC55357). [PMID](/source/PMID_(identifier)) [11459929](https://pubmed.ncbi.nlm.nih.gov/11459929).

1. **[^](#cite_ref-Xie_and_Miller_2009_156-0)** Xie Z, Miller GM (July 2009). ["A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700171). *J. Pharmacol. Exp. Ther*. **330** (1): 316–325. [doi](/source/Doi_(identifier)):[10.1124/jpet.109.153775](https://doi.org/10.1124%2Fjpet.109.153775). [PMC](/source/PMC_(identifier)) [2700171](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700171). [PMID](/source/PMID_(identifier)) [19364908](https://pubmed.ncbi.nlm.nih.gov/19364908).

1. **[^](#cite_ref-TAAR1_IUPHAR_157-0)** Maguire JJ, Davenport AP (2 December 2014). ["TA1 receptor"](http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=364). *IUPHAR database*. International Union of Basic and Clinical Pharmacology. [Archived](https://web.archive.org/web/20150629065449/http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=364) from the original on 29 June 2015. Retrieved 8 December 2014.

1. **[^](#cite_ref-EAAT3_158-0)** Underhill SM, Wheeler DS, Li M, Watts SD, Ingram SL, Amara SG (July 2014). ["Amphetamine modulates excitatory neurotransmission through endocytosis of the glutamate transporter EAAT3 in dopamine neurons"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159050). *Neuron*. **83** (2): 404–416. [doi](/source/Doi_(identifier)):[10.1016/j.neuron.2014.05.043](https://doi.org/10.1016%2Fj.neuron.2014.05.043). [PMC](/source/PMC_(identifier)) [4159050](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159050). [PMID](/source/PMID_(identifier)) [25033183](https://pubmed.ncbi.nlm.nih.gov/25033183). AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012).

1. **[^](#cite_ref-DAT_regulation_review_159-0)** Vaughan RA, Foster JD (September 2013). ["Mechanisms of dopamine transporter regulation in normal and disease states"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831354). *Trends Pharmacol. Sci*. **34** (9): 489–496. [doi](/source/Doi_(identifier)):[10.1016/j.tips.2013.07.005](https://doi.org/10.1016%2Fj.tips.2013.07.005). [PMC](/source/PMC_(identifier)) [3831354](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831354). [PMID](/source/PMID_(identifier)) [23968642](https://pubmed.ncbi.nlm.nih.gov/23968642). AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].

1. **[^](#cite_ref-GIRK_160-0)** Ledonne A, Berretta N, Davoli A, Rizzo GR, Bernardi G, Mercuri NB (July 2011). ["Electrophysiological effects of trace amines on mesencephalic dopaminergic neurons"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131148). *Front. Syst. Neurosci*. **5**: 56. [doi](/source/Doi_(identifier)):[10.3389/fnsys.2011.00056](https://doi.org/10.3389%2Ffnsys.2011.00056). [PMC](/source/PMC_(identifier)) [3131148](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131148). [PMID](/source/PMID_(identifier)) [21772817](https://pubmed.ncbi.nlm.nih.gov/21772817). inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.

1. **[^](#cite_ref-Genatlas_TAAR1_161-0)** mct (28 January 2012). ["TAAR1"](http://genatlas.medecine.univ-paris5.fr/fiche.php?symbol=TAAR1). *GenAtlas*. University of Paris. [Archived](https://web.archive.org/web/20140529150342/http://genatlas.medecine.univ-paris5.fr/fiche.php?symbol=TAAR1) from the original on 29 May 2014. Retrieved 29 May 2014. • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)

1. **[^](#cite_ref-TAAR1-Paradoxical_162-0)** Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, et al. (May 2011). ["TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101002). *Proc. Natl. Acad. Sci. U.S.A*. **108** (20): 8485–8490. [Bibcode](/source/Bibcode_(identifier)):[2011PNAS..108.8485R](https://ui.adsabs.harvard.edu/abs/2011PNAS..108.8485R). [doi](/source/Doi_(identifier)):[10.1073/pnas.1103029108](https://doi.org/10.1073%2Fpnas.1103029108). [PMC](/source/PMC_(identifier)) [3101002](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101002). [PMID](/source/PMID_(identifier)) [21525407](https://pubmed.ncbi.nlm.nih.gov/21525407).

1. ^ [***a***](#cite_ref-Meth_Transporters_163-0) [***b***](#cite_ref-Meth_Transporters_163-1) ["Methamphetamine: Transporters"](http://www.drugbank.ca/drugs/DB01577#transporters). *DrugBank*. University of Alberta. 8 February 2013. [Archived](https://web.archive.org/web/20151228164940/http://www.drugbank.ca/drugs/DB01577#transporters) from the original on 28 December 2015. Retrieved 4 January 2014.

1. **[^](#cite_ref-164)** Sulzer D, Sonders MS, Poulsen NW, Galli A (April 2005). "Mechanisms of neurotransmitter release by amphetamines: a review". *Progress in Neurobiology*. **75** (6): 406–433. [doi](/source/Doi_(identifier)):[10.1016/j.pneurobio.2005.04.003](https://doi.org/10.1016%2Fj.pneurobio.2005.04.003). [PMID](/source/PMID_(identifier)) [15955613](https://pubmed.ncbi.nlm.nih.gov/15955613). They also demonstrated competition for binding between METH and reserpine, suggesting they might bind to the same site on VMAT. George Uhl's laboratory similarly reported that AMPH displaced the VMAT2 blocker tetrabenazine (Gonzalez et al., 1994). Tetrabenazine and reserpine are thought to bind to different sites on VMAT (Schuldiner et al., 1993a)

1. **[^](#cite_ref-E_Weihe_165-0)** Eiden LE, Weihe E (January 2011). ["VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183197). *Ann. N. Y. Acad. Sci*. **1216** (1): 86–98. [Bibcode](/source/Bibcode_(identifier)):[2011NYASA1216...86E](https://ui.adsabs.harvard.edu/abs/2011NYASA1216...86E). [doi](/source/Doi_(identifier)):[10.1111/j.1749-6632.2010.05906.x](https://doi.org/10.1111%2Fj.1749-6632.2010.05906.x). [PMC](/source/PMC_(identifier)) [4183197](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183197). [PMID](/source/PMID_(identifier)) [21272013](https://pubmed.ncbi.nlm.nih.gov/21272013).

1. **[^](#cite_ref-pmid13677912_166-0)** Inazu M, Takeda H, Matsumiya T (August 2003). "[The role of glial monoamine transporters in the central nervous system]". *Nihon Shinkei Seishin Yakurigaku Zasshi* (in Japanese). **23** (4): 171–178. [PMID](/source/PMID_(identifier)) [13677912](https://pubmed.ncbi.nlm.nih.gov/13677912).

1. **[^](#cite_ref-Melega_167-0)** Melega WP, Cho AK, Schmitz D, Kuczenski R, Segal DS (February 1999). "l-methamphetamine pharmacokinetics and pharmacodynamics for assessment of in vivo deprenyl-derived l-methamphetamine". *J. Pharmacol. Exp. Ther*. **288** (2): 752–758. [doi](/source/Doi_(identifier)):[10.1016/S0022-3565(24)38016-4](https://doi.org/10.1016%2FS0022-3565%2824%2938016-4). [PMID](/source/PMID_(identifier)) [9918585](https://pubmed.ncbi.nlm.nih.gov/9918585).

1. ^ [***a***](#cite_ref-Kuczenski_168-0) [***b***](#cite_ref-Kuczenski_168-1) Kuczenski R, Segal DS, Cho AK, Melega W (February 1995). ["Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6577819). *J. Neurosci*. **15** (2): 1308–1317. [doi](/source/Doi_(identifier)):[10.1523/jneurosci.15-02-01308.1995](https://doi.org/10.1523%2Fjneurosci.15-02-01308.1995). [PMC](/source/PMC_(identifier)) [6577819](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6577819). [PMID](/source/PMID_(identifier)) [7869099](https://pubmed.ncbi.nlm.nih.gov/7869099).

1. ^ [***a***](#cite_ref-Mendelson_169-0) [***b***](#cite_ref-Mendelson_169-1) Mendelson J, Uemura N, Harris D, Nath RP, Fernandez E, Jacob P, et al. (October 2006). "Human pharmacology of the methamphetamine stereoisomers". *Clin. Pharmacol. Ther*. **80** (4): 403–420. [doi](/source/Doi_(identifier)):[10.1016/j.clpt.2006.06.013](https://doi.org/10.1016%2Fj.clpt.2006.06.013). [PMID](/source/PMID_(identifier)) [17015058](https://pubmed.ncbi.nlm.nih.gov/17015058).

1. ^ [***a***](#cite_ref-DrugBank_methamphetamine_metabolism_170-0) [***b***](#cite_ref-DrugBank_methamphetamine_metabolism_170-1) [***c***](#cite_ref-DrugBank_methamphetamine_metabolism_170-2) [***d***](#cite_ref-DrugBank_methamphetamine_metabolism_170-3) [***e***](#cite_ref-DrugBank_methamphetamine_metabolism_170-4) [***f***](#cite_ref-DrugBank_methamphetamine_metabolism_170-5) [***g***](#cite_ref-DrugBank_methamphetamine_metabolism_170-6) [***h***](#cite_ref-DrugBank_methamphetamine_metabolism_170-7) [***i***](#cite_ref-DrugBank_methamphetamine_metabolism_170-8) [***j***](#cite_ref-DrugBank_methamphetamine_metabolism_170-9) [***k***](#cite_ref-DrugBank_methamphetamine_metabolism_170-10) ["Methamphetamine: Pharmacology"](https://www.drugbank.ca/drugs/DB01577#pharmacology). *DrugBank*. University of Alberta. 2 October 2017. [Archived](https://web.archive.org/web/20171006012111/https://www.drugbank.ca/drugs/DB01577#pharmacology) from the original on 6 October 2017. Retrieved 5 October 2017. Methamphetamine is rapidly absorbed from the gastrointestinal tract with peak methamphetamine concentrations occurring in 3.13 to 6.3 hours post ingestion. Methamphetamine is also well absorbed following inhalation and following intranasal administration. It is distributed to most parts of the body. Because methamphetamine has a high lipophilicity it is distributed across the blood brain barrier and crosses the placenta. ... The primary site of metabolism is in the liver by aromatic hydroxylation, N-dealkylation and deamination. At least seven metabolites have been identified in the urine, with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine. Other minor metabolites include 4-hydroxyamphetamine, norephedrine, and 4-hydroxynorephedrine.

1. **[^](#cite_ref-pmid30731099_171-0)** Xu J, Zhang Z, Liu R, Sun Y, Liu H, Nie Z, et al. (May 2019). "Function of complement factor H and imaging of small molecules by MALDI-MSI in a methamphetamine behavioral sensitization model". *Behavioural Brain Research*. **364**: 233–244. [doi](/source/Doi_(identifier)):[10.1016/j.bbr.2019.02.002](https://doi.org/10.1016%2Fj.bbr.2019.02.002). [PMID](/source/PMID_(identifier)) [30731099](https://pubmed.ncbi.nlm.nih.gov/30731099). Methamphetamine (METH) is a potent amphetamine-type stimulant that has high abuse potential and can be smoked, snorted, injected, or taken orally. The drug is high in lipid solubility and can cross the blood-brain barrier more readily than amphetamine due to the addition of an extra methyl group.

1. ^ [***a***](#cite_ref-Metabolites_172-0) [***b***](#cite_ref-Metabolites_172-1) Santagati NA, Ferrara G, Marrazzo A, Ronsisvalle G (September 2002). "Simultaneous determination of amphetamine and one of its metabolites by HPLC with electrochemical detection". *J. Pharm. Biomed. Anal*. **30** (2): 247–255. [doi](/source/Doi_(identifier)):[10.1016/S0731-7085(02)00330-8](https://doi.org/10.1016%2FS0731-7085%2802%2900330-8). [PMID](/source/PMID_(identifier)) [12191709](https://pubmed.ncbi.nlm.nih.gov/12191709).

1. **[^](#cite_ref-Substituted_amphetamines,_FMO,_and_DBH_173-0)** Glennon RA (2013). ["Phenylisopropylamine stimulants: amphetamine-related agents"](https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA646). In Lemke TL, Williams DA, Roche VF, Zito W (eds.). *Foye's principles of medicinal chemistry* (7th ed.). Philadelphia, USA: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. [ISBN](/source/ISBN_(identifier)) [978-1-60913-345-0](https://en.wikipedia.org/wiki/Special:BookSources/978-1-60913-345-0). [Archived](https://web.archive.org/web/20230113011526/https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA646) from the original on 13 January 2023. Retrieved 5 October 2017. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to *p*-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords *p*-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.

1. **[^](#cite_ref-DBH_amph_primary_174-0)** Taylor KB (January 1974). ["Dopamine-beta-hydroxylase. Stereochemical course of the reaction"](http://www.jbc.org/content/249/2/454.full.pdf) (PDF). *J. Biol. Chem*. **249** (2): 454–458. [doi](/source/Doi_(identifier)):[10.1016/S0021-9258(19)43051-2](https://doi.org/10.1016%2FS0021-9258%2819%2943051-2). [PMID](/source/PMID_(identifier)) [4809526](https://pubmed.ncbi.nlm.nih.gov/4809526). [Archived](https://web.archive.org/web/20181007182156/http://www.jbc.org/content/249/2/454.full.pdf) (PDF) from the original on 7 October 2018. Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.

1. **[^](#cite_ref-pmid13977820_175-0)** Sjoerdsma A, von Studnitz W (April 1963). ["Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1703637). *Br. J. Pharmacol. Chemother*. **20** (2): 278–284. [doi](/source/Doi_(identifier)):[10.1111/j.1476-5381.1963.tb01467.x](https://doi.org/10.1111%2Fj.1476-5381.1963.tb01467.x). [PMC](/source/PMC_(identifier)) [1703637](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1703637). [PMID](/source/PMID_(identifier)) [13977820](https://pubmed.ncbi.nlm.nih.gov/13977820). Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.

1. **[^](#cite_ref-Benzoic1_176-0)** ["butyrate-CoA ligase: Substrate/Product"](http://www.brenda-enzymes.info/enzyme.php?ecno=6.2.1.2&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0). *BRENDA*. Technische Universität Braunschweig. [Archived](https://web.archive.org/web/20170622234353/http://www.brenda-enzymes.info/enzyme.php?ecno=6.2.1.2&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0) from the original on 22 June 2017. Retrieved 5 October 2017.

1. **[^](#cite_ref-Benzoic2_177-0)** ["glycine N-acyltransferase: Substrate/Product"](http://www.brenda-enzymes.info/enzyme.php?ecno=2.3.1.13&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0). *BRENDA*. Technische Universität Braunschweig. [Archived](https://web.archive.org/web/20170623000309/http://www.brenda-enzymes.info/enzyme.php?ecno=2.3.1.13&Suchword=&organism%5B%5D=Homo+sapiens&show_tm=0) from the original on 23 June 2017. Retrieved 5 October 2017.

1. **[^](#cite_ref-179)** ["p-Hydroxyamphetamine: Compound Summary"](https://pubchem.ncbi.nlm.nih.gov/compound/3651). *PubChem Compound*. National Center for Biotechnology Information. [Archived](https://web.archive.org/web/20130607202440/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3651) from the original on 7 June 2013. Retrieved 4 September 2017.

1. **[^](#cite_ref-180)** ["p-Hydroxynorephedrine: Compound Summary"](https://pubchem.ncbi.nlm.nih.gov/compound/11099). *PubChem Compound*. National Center for Biotechnology Information. [Archived](https://web.archive.org/web/20131015073126/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=11099) from the original on 15 October 2013. Retrieved 4 September 2017.

1. **[^](#cite_ref-181)** ["Phenylpropanolamine: Compound Summary"](https://pubchem.ncbi.nlm.nih.gov/compound/26934). *PubChem Compound*. National Center for Biotechnology Information. [Archived](https://web.archive.org/web/20130929154657/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=26934) from the original on 29 September 2013. Retrieved 4 September 2017.

1. **[^](#cite_ref-Pubchem_Kinetics_182-0)** ["Amphetamine"](https://pubchem.ncbi.nlm.nih.gov/compound/3007). *Pubchem Compound*. National Center for Biotechnology Information. [Archived](https://web.archive.org/web/20131013122604/http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3007) from the original on 13 October 2013. Retrieved 12 October 2013.

1. **[^](#cite_ref-Meth_demethylation_review_183-0)** Haiser HJ, Turnbaugh PJ (March 2013). ["Developing a metagenomic view of xenobiotic metabolism"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526672). *Pharmacol. Res*. **69** (1): 21–31. [doi](/source/Doi_(identifier)):[10.1016/j.phrs.2012.07.009](https://doi.org/10.1016%2Fj.phrs.2012.07.009). [PMC](/source/PMC_(identifier)) [3526672](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526672). [PMID](/source/PMID_(identifier)) [22902524](https://pubmed.ncbi.nlm.nih.gov/22902524). Haiser HJ, Turnbaugh PJ (March 2013). ["Table 2: Xenobiotics metabolized by the human gut microbiota"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526672). *Pharmacological Research*. **69** (1): 21–31. [doi](/source/Doi_(identifier)):[10.1016/j.phrs.2012.07.009](https://doi.org/10.1016%2Fj.phrs.2012.07.009). [PMC](/source/PMC_(identifier)) [3526672](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3526672). [PMID](/source/PMID_(identifier)) [22902524](https://pubmed.ncbi.nlm.nih.gov/22902524).

1. **[^](#cite_ref-Meth_demethylation_primary_184-0)** Caldwell J, Hawksworth GM (May 1973). "The demethylation of methamphetamine by intestinal microflora". *The Journal of Pharmacy and Pharmacology*. **25** (5): 422–424. [doi](/source/Doi_(identifier)):[10.1111/j.2042-7158.1973.tb10043.x](https://doi.org/10.1111%2Fj.2042-7158.1973.tb10043.x). [PMID](/source/PMID_(identifier)) [4146404](https://pubmed.ncbi.nlm.nih.gov/4146404).

1. **[^](#cite_ref-Ergogenics_185-0)** Liddle DG, Connor DJ (June 2013). "Nutritional supplements and ergogenic AIDS". *Prim. Care*. **40** (2): 487–505. [doi](/source/Doi_(identifier)):[10.1016/j.pop.2013.02.009](https://doi.org/10.1016%2Fj.pop.2013.02.009). [PMID](/source/PMID_(identifier)) [23668655](https://pubmed.ncbi.nlm.nih.gov/23668655).

1. **[^](#cite_ref-pmid9700558_186-0)** Kraemer T, Maurer HH (August 1998). "Determination of amphetamine, methamphetamine and amphetamine-derived designer drugs or medicaments in blood and urine". *J. Chromatogr. B*. **713** (1): 163–187. [doi](/source/Doi_(identifier)):[10.1016/S0378-4347(97)00515-X](https://doi.org/10.1016%2FS0378-4347%2897%2900515-X). [PMID](/source/PMID_(identifier)) [9700558](https://pubmed.ncbi.nlm.nih.gov/9700558).

1. **[^](#cite_ref-pmid17468860_187-0)** Kraemer T, Paul LD (August 2007). "Bioanalytical procedures for determination of drugs of abuse in blood". *Anal. Bioanal. Chem*. **388** (7): 1415–1435. [doi](/source/Doi_(identifier)):[10.1007/s00216-007-1271-6](https://doi.org/10.1007%2Fs00216-007-1271-6). [PMID](/source/PMID_(identifier)) [17468860](https://pubmed.ncbi.nlm.nih.gov/17468860).

1. **[^](#cite_ref-pmid8075776_188-0)** Goldberger BA, Cone EJ (July 1994). "Confirmatory tests for drugs in the workplace by gas chromatography-mass spectrometry". *J. Chromatogr. A*. **674** (1–2): 73–86. [doi](/source/Doi_(identifier)):[10.1016/0021-9673(94)85218-9](https://doi.org/10.1016%2F0021-9673%2894%2985218-9). [PMID](/source/PMID_(identifier)) [8075776](https://pubmed.ncbi.nlm.nih.gov/8075776).

1. ^ [***a***](#cite_ref-pmid15516295_189-0) [***b***](#cite_ref-pmid15516295_189-1) Paul BD, Jemionek J, Lesser D, Jacobs A, Searles DA (September 2004). ["Enantiomeric separation and quantitation of (+/-)-amphetamine, (+/-)-methamphetamine, (+/-)-MDA, (+/-)-MDMA, and (+/-)-MDEA in urine specimens by GC-EI-MS after derivatization with (R)-(−)- or (S)-(+)-alpha-methoxy-alpha-(trifluoromethy)phenylacetyl chloride (MTPA)"](https://doi.org/10.1093%2Fjat%2F28.6.449). *J. Anal. Toxicol*. **28** (6): 449–455. [doi](/source/Doi_(identifier)):[10.1093/jat/28.6.449](https://doi.org/10.1093%2Fjat%2F28.6.449). [PMID](/source/PMID_(identifier)) [15516295](https://pubmed.ncbi.nlm.nih.gov/15516295).

1. **[^](#cite_ref-pmid14871155_190-0)** de la Torre R, Farré M, Navarro M, Pacifici R, Zuccaro P, Pichini S (2004). "Clinical pharmacokinetics of amfetamine and related substances: monitoring in conventional and non-conventional matrices". *Clin Pharmacokinet*. **43** (3): 157–185. [doi](/source/Doi_(identifier)):[10.2165/00003088-200443030-00002](https://doi.org/10.2165%2F00003088-200443030-00002). [PMID](/source/PMID_(identifier)) [14871155](https://pubmed.ncbi.nlm.nih.gov/14871155).

1. **[^](#cite_ref-191)** Baselt RC (2020). *Disposition of toxic drugs and chemicals in man*. Seal Beach, Ca.: Biomedical Publications. pp. 1277–1280. [ISBN](/source/ISBN_(identifier)) [978-0-578-57749-4](https://en.wikipedia.org/wiki/Special:BookSources/978-0-578-57749-4).

1. **[^](#cite_ref-pmid21740689_192-0)** Venkatratnam A, Lents NH (July 2011). "Zinc reduces the detection of cocaine, methamphetamine, and THC by ELISA urine testing". *J. Anal. Toxicol*. **35** (6): 333–340. [doi](/source/Doi_(identifier)):[10.1093/anatox/35.6.333](https://doi.org/10.1093%2Fanatox%2F35.6.333). [PMID](/source/PMID_(identifier)) [21740689](https://pubmed.ncbi.nlm.nih.gov/21740689).

1. **[^](#cite_ref-193)** Hakey P, Ouellette W, Zubieta J, Korter T (April 2008). ["Redetermination of (+)-methamphetamine hydro-chloride at 90 K"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2961146). *Acta Crystallographica Section E*. **64** (Pt 5): o940. [Bibcode](/source/Bibcode_(identifier)):[2008AcCrE..64O.940H](https://ui.adsabs.harvard.edu/abs/2008AcCrE..64O.940H). [doi](/source/Doi_(identifier)):[10.1107/S1600536808011550](https://doi.org/10.1107%2FS1600536808011550). [PMC](/source/PMC_(identifier)) [2961146](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2961146). [PMID](/source/PMID_(identifier)) [21202421](https://pubmed.ncbi.nlm.nih.gov/21202421).

1. **[^](#cite_ref-194)** Nakayama MT. ["Chemical Interaction of Bleach and Methamphetamine: A Study of Degradation and Transformation Effects"](https://web.archive.org/web/20141019005517/http://gradworks.umi.com/14/93/1493688.html). *gradworks*. UNIVERSITY OF CALIFORNIA, DAVIS. Archived from [the original](http://gradworks.umi.com/14/93/1493688.html) on 19 October 2014. Retrieved 17 October 2014.

1. **[^](#cite_ref-pmid21777940_195-0)** Pal R, Megharaj M, Kirkbride KP, Heinrich T, Naidu R (October 2011). "Biotic and abiotic degradation of illicit drugs, their precursor, and by-products in soil". *Chemosphere*. **85** (6): 1002–9. [Bibcode](/source/Bibcode_(identifier)):[2011Chmsp..85.1002P](https://ui.adsabs.harvard.edu/abs/2011Chmsp..85.1002P). [doi](/source/Doi_(identifier)):[10.1016/j.chemosphere.2011.06.102](https://doi.org/10.1016%2Fj.chemosphere.2011.06.102). [PMID](/source/PMID_(identifier)) [21777940](https://pubmed.ncbi.nlm.nih.gov/21777940).

1. **[^](#cite_ref-pmid23886544_196-0)** Bagnall J, Malia L, Lubben A, Kasprzyk-Hordern B (October 2013). ["Stereoselective biodegradation of amphetamine and methamphetamine in river microcosms"](https://doi.org/10.1016%2Fj.watres.2013.06.057). *Water Res*. **47** (15): 5708–18. [Bibcode](/source/Bibcode_(identifier)):[2013WatRe..47.5708B](https://ui.adsabs.harvard.edu/abs/2013WatRe..47.5708B). [doi](/source/Doi_(identifier)):[10.1016/j.watres.2013.06.057](https://doi.org/10.1016%2Fj.watres.2013.06.057). [PMID](/source/PMID_(identifier)) [23886544](https://pubmed.ncbi.nlm.nih.gov/23886544).

1. **[^](#cite_ref-Crossley_1944_197-0)** Crossley FS, Moore ML (November 1944). "Studies on the Leuckart reaction". *The Journal of Organic Chemistry*. **9** (6): 529–536. [doi](/source/Doi_(identifier)):[10.1021/jo01188a006](https://doi.org/10.1021%2Fjo01188a006).

1. ^ [***a***](#cite_ref-pmid19637924_198-0) [***b***](#cite_ref-pmid19637924_198-1) [***c***](#cite_ref-pmid19637924_198-2) [***d***](#cite_ref-pmid19637924_198-3) [***e***](#cite_ref-pmid19637924_198-4) Kunalan V, Nic Daéid N, Kerr WJ, Buchanan HA, McPherson AR (September 2009). ["Characterization of route specific impurities found in methamphetamine synthesized by the Leuckart and reductive amination methods"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662403). *Anal. Chem*. **81** (17): 7342–7348. [Bibcode](/source/Bibcode_(identifier)):[2009AnaCh..81.7342K](https://ui.adsabs.harvard.edu/abs/2009AnaCh..81.7342K). [doi](/source/Doi_(identifier)):[10.1021/ac9005588](https://doi.org/10.1021%2Fac9005588). [PMC](/source/PMC_(identifier)) [3662403](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662403). [PMID](/source/PMID_(identifier)) [19637924](https://pubmed.ncbi.nlm.nih.gov/19637924).

1. **[^](#cite_ref-NIDA-deaths_199-0)** ["Overdose Death Rates"](https://web.archive.org/web/20171213234138/https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates). *[National Institute on Drug Abuse](/source/National_Institute_on_Drug_Abuse) (NIDA)*. Archived from [the original](https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates) on 13 December 2017.

1. **[^](#cite_ref-200)** ["US overdose deaths from fentanyl and synthetic opioids doubled in 2016"](https://www.theguardian.com/us-news/2017/sep/03/fentanyl-synthetic-opioids-deaths-doubled-us). *The Guardian*. 3 September 2017. [Archived](https://web.archive.org/web/20180817225855/https://www.theguardian.com/us-news/2017/sep/03/fentanyl-synthetic-opioids-deaths-doubled-us) from the original on 17 August 2018. Retrieved 17 August 2018.

1. **[^](#cite_ref-201)** Rassool GH (2009). *Alcohol and Drug Misuse: A Handbook for Students and Health Professionals*. London: Routledge. p. 113. [ISBN](/source/ISBN_(identifier)) [978-0-203-87117-1](https://en.wikipedia.org/wiki/Special:BookSources/978-0-203-87117-1).

1. ^ [***a***](#cite_ref-Vermont_202-0) [***b***](#cite_ref-Vermont_202-1) ["Historical overview of methamphetamine"](http://healthvermont.gov/adap/meth/brief_history.aspx). *Vermont Department of Health*. Government of Vermont. [Archived](https://web.archive.org/web/20120620083221/http://healthvermont.gov/adap/meth/brief_history.aspx) from the original on 20 June 2012. Retrieved 29 January 2012.

1. **[^](#cite_ref-Grobler_et_al_2011_203-0)** Grobler SR, Chikte U, Westraat J (2011). ["The pH Levels of Different Methamphetamine Drug Samples on the Street Market in Cape Town"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189445). *ISRN Dentistry*. **2011**: 1–4. [doi](/source/Doi_(identifier)):[10.5402/2011/974768](https://doi.org/10.5402%2F2011%2F974768). [PMC](/source/PMC_(identifier)) [3189445](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189445). [PMID](/source/PMID_(identifier)) [21991491](https://pubmed.ncbi.nlm.nih.gov/21991491).

1. **[^](#cite_ref-history_204-0)** ["Historical overview of methamphetamine"](http://healthvermont.gov/adap/meth/brief_history.aspx). Vermont Department of Health. [Archived](https://web.archive.org/web/20120620083221/http://healthvermont.gov/adap/meth/brief_history.aspx) from the original on 20 June 2012. Retrieved 15 January 2012.

1. **[^](#cite_ref-CISP_205-0)** [*Pervitin*](http://www.chemie.de/lexikon/Pervitin.html) (in German), Berlin: CHEMIE.DE Information Service GmbH, [archived](https://web.archive.org/web/20191218224238/https://www.chemie.de/lexikon/Pervitin.html) from the original on 18 December 2019, retrieved 16 September 2015

1. **[^](#cite_ref-206)** Freye E (2009). *Pharmacology and Abuse of Cocaine, Amphetamines, Ecstasy and Related Designer Drugs*. University Düsseldorf, Germany: Springer. p. 110. [ISBN](/source/ISBN_(identifier)) [978-90-481-2447-3](https://en.wikipedia.org/wiki/Special:BookSources/978-90-481-2447-3).

1. **[^](#cite_ref-207)** Ulrich A (6 May 2005). ["The Nazi Death Machine: Hitler's Drugged Soldiers"](http://www.spiegel.de/international/the-nazi-death-machine-hitler-s-drugged-soldiers-a-354606.html). *Spiegel Online*. Der Spiegel, 6 May 2005. [Archived](https://web.archive.org/web/20171219062055/http://www.spiegel.de/international/the-nazi-death-machine-hitler-s-drugged-soldiers-a-354606.html) from the original on 19 December 2017. Retrieved 12 August 2014.

1. **[^](#cite_ref-pmid22849208_208-0)** Defalque RJ, Wright AJ (April 2011). "Methamphetamine for Hitler's Germany: 1937 to 1945". *Bull. Anesth. Hist*. **29** (2): 21–24, 32. [doi](/source/Doi_(identifier)):[10.1016/s1522-8649(11)50016-2](https://doi.org/10.1016%2Fs1522-8649%2811%2950016-2). [PMID](/source/PMID_(identifier)) [22849208](https://pubmed.ncbi.nlm.nih.gov/22849208).

1. ^ [***a***](#cite_ref-shooting_up_209-0) [***b***](#cite_ref-shooting_up_209-1) Kamieński Ł (2016). [*Shooting Up: A Short History of Drugs and War*](https://books.google.com/books?id=NAVCCwAAQBAJ&pg=PA112). Oxford University Press. pp. 111–13. [ISBN](/source/ISBN_(identifier)) [978-0-19-026347-8](https://en.wikipedia.org/wiki/Special:BookSources/978-0-19-026347-8). [Archived](https://web.archive.org/web/20170323182238/https://books.google.com/books?id=NAVCCwAAQBAJ&pg=PA112) from the original on 23 March 2017. Retrieved 23 October 2016.

1. ^ [***a***](#cite_ref-Real_Obetrol_Ad_210-0) [***b***](#cite_ref-Real_Obetrol_Ad_210-1) Rasmussen N (March 2008). *On Speed: The Many Lives of Amphetamine* (1 ed.). New York University Press. p. 148. [ISBN](/source/ISBN_(identifier)) [978-0-8147-7601-8](https://en.wikipedia.org/wiki/Special:BookSources/978-0-8147-7601-8).

1. **[^](#cite_ref-211)** Admin (2 May 2013). ["Recordati: Desoxyn"](https://web.archive.org/web/20130707013757/http://www.recordatirarediseases.com/products/us-product/desoxyn%C2%AE-cii-methamphetamine-hydrochloride-tablets-usp). *Recordati Rare Diseases*. Recordati SP. Archived from [the original](http://www.recordatirarediseases.com/products/us-product/desoxyn%C2%AE-cii-methamphetamine-hydrochloride-tablets-usp) on 7 July 2013. Retrieved 15 May 2013.

1. **[^](#cite_ref-212)** ["Transnational Organized Crime in Southeast Asia: Evolution, Growth and Challenges"](https://web.archive.org/web/20210122015018/https://www.unodc.org/documents/southeastasiaandpacific/Publications/2019/SEA_TOCTA_2019_web.pdf) (PDF). June 2019. Archived from [the original](https://www.unodc.org/documents/southeastasiaandpacific/Publications/2019/SEA_TOCTA_2019_web.pdf/) on 22 January 2021. Retrieved 30 July 2020.

1. **[^](#cite_ref-213)** ["The Man Accused of Running the Biggest Drug Trafficking Syndicate in Asia's History has Been Revealed: Here's What Needs To Happen Next"](https://edition.cnn.com/2019/10/23/opinions/tse-chi-lop-revealed-opinion-intl-hnk/index.html). [CNN](/source/CNN). 24 October 2019. [Archived](https://web.archive.org/web/20211022232716/https://edition.cnn.com/2019/10/23/opinions/tse-chi-lop-revealed-opinion-intl-hnk/index.html) from the original on 22 October 2021. Retrieved 30 July 2020.

1. **[^](#cite_ref-214)** Smith N (14 October 2019). ["Drugs investigators close in on Asian 'El Chapo' at centre of vast meth ring"](https://www.telegraph.co.uk/news/2019/10/14/drugs-investigators-close-asian-el-chapo-centre-vast-meth-ring/). *The Telegraph*. [Archived](https://ghostarchive.org/archive/20220110/https://www.telegraph.co.uk/news/2019/10/14/drugs-investigators-close-asian-el-chapo-centre-vast-meth-ring/) from the original on 10 January 2022.

1. **[^](#cite_ref-215)** ["Inside the hunt for the man known as 'Asia's El Chapo'"](https://nypost.com/2019/10/14/inside-the-hunt-for-the-man-known-as-asias-el-chapo/). *[New York Post](/source/New_York_Post)*. 14 October 2019. [Archived](https://web.archive.org/web/20210119003851/https://nypost.com/2019/10/14/inside-the-hunt-for-the-man-known-as-asias-el-chapo/) from the original on 19 January 2021. Retrieved 30 July 2020.

1. ^ [***a***](#cite_ref-:0_216-0) [***b***](#cite_ref-:0_216-1) ["Notorious drug kingpin executed for trafficking"](https://www.scmp.com/article/692604/notorious-drug-kingpin-executed-trafficking). *South China Morning Post*. 16 September 2009. [Archived](https://web.archive.org/web/20220603092530/https://www.scmp.com/article/692604/notorious-drug-kingpin-executed-trafficking) from the original on 3 June 2022. Retrieved 3 June 2022.

1. **[^](#cite_ref-217)** United Nations Office on Drugs and Crime (2007). [*Preventing Amphetamine-type Stimulant Use Among Young People: A Policy and Programming Guide*](http://www.unodc.org/pdf/youthnet/ATS.pdf) (PDF). New York: United Nations. [ISBN](/source/ISBN_(identifier)) [978-92-1-148223-2](https://en.wikipedia.org/wiki/Special:BookSources/978-92-1-148223-2). [Archived](https://web.archive.org/web/20131016082310/http://www.unodc.org/pdf/youthnet/ATS.pdf) (PDF) from the original on 16 October 2013. Retrieved 11 November 2013.

1. ^ [***a***](#cite_ref-incb_218-0) [***b***](#cite_ref-incb_218-1) ["List of psychotropic substances under international control"](https://web.archive.org/web/20051205125434/http://www.incb.org/pdf/e/list/green.pdf) (PDF). *International Narcotics Control Board*. United Nations. August 2003. Archived from [the original](http://www.incb.org/pdf/e/list/green.pdf) (PDF) on 5 December 2005. Retrieved 19 November 2005.

1. **[^](#cite_ref-219)** Rau TF, Kothiwal AS, Rova AR, Brooks DM, Poulsen DJ (August 2012). "Treatment with low-dose methamphetamine improves behavioral and cognitive function after severe traumatic brain injury". *The Journal of Trauma and Acute Care Surgery*. **73** (2 Suppl 1): S165–S172. [doi](/source/Doi_(identifier)):[10.1097/TA.0b013e318260896a](https://doi.org/10.1097%2FTA.0b013e318260896a). [PMID](/source/PMID_(identifier)) [22847088](https://pubmed.ncbi.nlm.nih.gov/22847088).

1. **[^](#cite_ref-220)** O'Phelan K, McArthur DL, Chang CW, Green D, Hovda DA (September 2008). "The impact of substance abuse on mortality in patients with severe traumatic brain injury". *The Journal of Trauma*. **65** (3): 674–677. [doi](/source/Doi_(identifier)):[10.1097/TA.0b013e31817db0a5](https://doi.org/10.1097%2FTA.0b013e31817db0a5). [PMID](/source/PMID_(identifier)) [18784583](https://pubmed.ncbi.nlm.nih.gov/18784583).

1. **[^](#cite_ref-221)** Cass WA, Smith MP, Peters LE (August 2006). "Calcitriol protects against the dopamine- and serotonin-depleting effects of neurotoxic doses of methamphetamine". *Annals of the New York Academy of Sciences*. **1074** (1): 261–271. [Bibcode](/source/Bibcode_(identifier)):[2006NYASA1074..261C](https://ui.adsabs.harvard.edu/abs/2006NYASA1074..261C). [doi](/source/Doi_(identifier)):[10.1196/annals.1369.023](https://doi.org/10.1196%2Fannals.1369.023). [PMID](/source/PMID_(identifier)) [17105922](https://pubmed.ncbi.nlm.nih.gov/17105922).

1. **[^](#cite_ref-222)** Huang YN, Yang LY, Wang JY, Lai CC, Chiu CT, Wang JY (January 2017). "L-Ascorbate Protects Against Methamphetamine-Induced Neurotoxicity of Cortical Cells via Inhibiting Oxidative Stress, Autophagy, and Apoptosis". *Molecular Neurobiology*. **54** (1): 125–136. [doi](/source/Doi_(identifier)):[10.1007/s12035-015-9561-z](https://doi.org/10.1007%2Fs12035-015-9561-z). [PMID](/source/PMID_(identifier)) [26732595](https://pubmed.ncbi.nlm.nih.gov/26732595).

1. **[^](#cite_ref-223)** Moshiri M, Hosseiniyan SM, Moallem SA, Hadizadeh F, Jafarian AH, Ghadiri A, et al. (April 2018). ["The effects of vitamin B12 on the brain damages caused by methamphetamine in mice"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960763). *Iranian Journal of Basic Medical Sciences*. **21** (4): 434–438. [doi](/source/Doi_(identifier)):[10.22038/IJBMS.2018.23362.5897](https://doi.org/10.22038%2FIJBMS.2018.23362.5897). [PMC](/source/PMC_(identifier)) [5960763](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960763). [PMID](/source/PMID_(identifier)) [29796230](https://pubmed.ncbi.nlm.nih.gov/29796230).

1. **[^](#cite_ref-224)** Anazodo G (May 2024). ["Protective effects of vitamin C and E on amygdala of methamphetamine-induced brain disorder on adult male Wistar rats"](https://wjpr.s3.ap-south-1.amazonaws.com/article_issue/eefe2451ff2a6848f0249c533e1fc88d.pdf) (PDF). *World Journal of Pharmaceutical Research*. **13** (9): 2121–2170. [Archived](https://web.archive.org/web/20240922021107/https://wjpr.s3.ap-south-1.amazonaws.com/article_issue/eefe2451ff2a6848f0249c533e1fc88d.pdf) (PDF) from the original on 22 September 2024. Retrieved 19 September 2024.

## Further reading

- Hart CL, Marvin CB, Silver R, Smith EE (February 2012). ["Is cognitive functioning impaired in methamphetamine users? A critical review"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260986). *Neuropsychopharmacology*. **37** (3): 586–608. [doi](/source/Doi_(identifier)):[10.1038/npp.2011.276](https://doi.org/10.1038%2Fnpp.2011.276). [PMC](/source/PMC_(identifier)) [3260986](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260986). [PMID](/source/PMID_(identifier)) [22089317](https://pubmed.ncbi.nlm.nih.gov/22089317).

- Rusyniak DE (August 2011). ["Neurologic manifestations of chronic methamphetamine abuse"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148451). *Neurologic Clinics*. **29** (3): 641–655. [doi](/source/Doi_(identifier)):[10.1016/j.ncl.2011.05.004](https://doi.org/10.1016%2Fj.ncl.2011.05.004). [PMC](/source/PMC_(identifier)) [3148451](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148451). [PMID](/source/PMID_(identifier)) [21803215](https://pubmed.ncbi.nlm.nih.gov/21803215).

- Szalavitz M (21 November 2011). ["Why the Myth of the Meth-Damaged Brain May Hinder Recovery"](https://healthland.time.com/2011/11/21/why-the-myth-of-the-meth-damaged-brain-may-hinder-recovery/). *Time*. [Archived](https://web.archive.org/web/20240922021109/https://healthland.time.com/2011/11/21/why-the-myth-of-the-meth-damaged-brain-may-hinder-recovery/) from the original on 22 September 2024. Retrieved 22 September 2024.

## External links

**Methamphetamine**  at Wikipedia's [sister projects](https://en.wikipedia.org/wiki/Wikipedia:Wikimedia_sister_projects)

- [Media](https://commons.wikimedia.org/wiki/Category:Dextromethamphetamine) from Commons
- [Data](https://www.wikidata.org/wiki/Q191924) from Wikidata

- [Methamphetamine Poison Information Monograph](https://www.inchem.org/documents/pims/pharm/pim334.htm)

- [Drug Trafficking: Aryan Brotherhood Methamphetamine Operation Dismantled](https://www.fbi.gov/news/stories/aryan-brotherhood-methamphetamine-operation-dismantled), [FBI](/source/FBI)

v t e Amphetamine Main articles and pharmaceuticals Amphetamine Adzenys ER Adzenys XR-ODT Dyanavel XR Evekeo Evekeo ODT Mixed amphetamine salts Adderall Adderall XR Mydayis Levoamphetamine N/A Dextroamphetamine Dexedrine ProCentra Zenzedi Lisdexamfetamine Vyvanse Neuropharmacology Biomolecular targets TAAR1 (full agonist) CART (mRNATooltip messenger RNA inducer) 5-HT1A receptor (low affinity ligand) MAO (weak competitive inhibitor) Carbonic anhydrases hCA4, hCA5A, hCA5B, hCA7, hCA12, hCA13, and hCA14 (enzyme activator) Inhibited transporters DAT NET SERT VMAT1 VMAT2 EAAT3 SLC22A3 SLC22A5 Active metabolites 4-Hydroxyamphetamine 4-Hydroxynorephedrine N-Hydroxyamphetamine Norephedrine Related articles ADHD ADHD management Amphetamine psychosis Benzedrine in popular culture Dopamine Doping in sport Executive functions Formetorex ΔFosB History and culture of substituted amphetamines Methamphetamine Methylphenidate N-Methylphenethylamine Motivational salience Incentive salience Narcolepsy Neurobiological effects of physical exercise § Attention deficit hyperactivity disorder Nootropic Norepinephrine Obesity Performance-enhancing substance Phenethylamine Phentermine Phenylacetone Recreational drug use Serotonin Substituted amphetamine Trace amine Category

v t e Methamphetamine Enantiomers Dextromethamphetamine Levomethamphetamine Neuropharmacology Biomolecular targets TAAR1 (agonist) σ1R (agonist) σ2R (agonist) α2A adrenoceptor (agonist) α2B adrenoceptor (agonist) α2C adrenoceptor (agonist) MAO (competitive inhibitor) Inhibited transporters DAT NET SERT VMAT1 VMAT2 EAAT1 EAAT2 SLC22A3 SLC22A5 Health Amphetamine dependence Meth mouth History and culture Amphetamine Crystal Darkness Crystal Meth Anonymous Faces of Meth History and culture of amphetamines Montana Meth Project No More Sunsets Party and play Rolling meth lab Ya ba Law Legal status Combat Methamphetamine Epidemic Act of 2005 Comprehensive Methamphetamine Control Act of 1996 Illinois Methamphetamine Precursor Control Act Ethnicity and nationality United States Native Americans Australia

v t e Recreational drug use Major recreational drugs Depressants Barbiturates Benzodiazepines Carbamates Ethanol (alcohol) Alcoholic beverage Beer Wine Gabapentinoids GHB Inhalants Medical Nitrous oxide (recreational use) Hazardous solvents contact adhesives Gasoline nail polish remover Paint thinner Other Freon Kava Nonbenzodiazepines Quinazolinones Quaaludes Opioids Buprenorphine Suboxone Subutex Codeine Lean Desomorphine Krokodil Dextropropoxyphene Darvocet Darvon Fentanyl Diamorphine Heroin Hydrocodone Hydromorphone Dilaudid Methadone Mitragyna speciosa Kratom Morphine Opium Oxycodone /paracetamol Tramadol Stimulants Amphetamine Arecoline Areca Betel Caffeine Coffee Energy drinks Tea Cathinone Khat Cocaine Coca Cocaine paste Crack Ephedrine Ephedra MDPV Mephedrone Methamphetamine Methylone Methylphenidate Modafinil Nicotine Polacrilex Salt Tobacco Theobromine Cocoa Chocolate Entactogens 2C series 6-APB Benzofury AMT MDA MDMA Ecstasy Molly Hallucinogens Psychedelics 2C-B 25I-NBOMe 4-AcO-DMT 5-MeO-DMT Psychoactive toads Bufotenin Vilca Yopo DMT Ayahuasca LSA and iso-LSA Morning glory Ergot LSD Mescaline Peruvian torch Peyote San Pedro Psilocybin and psilocin Psilocybin mushrooms Dissociatives DXM (recreational use) Inhalants Nitrous oxide (recreational use) Ketamine MXE PCP Deliriants Atropine and Scopolamine Atropa belladonna Datura Hyoscyamus niger Mandragora officinarum Dimenhydrinate Diphenhydramine Cannabinoids THC Cannabis (Marijuana) Hashish Hash oil Synthetic cannabinoids JWH-018 APICA APINACA Spice Others Ibogaine Tabernanthe iboga Muscimol Amanita muscaria Oneirogens Calea zacatechichi Silene capensis Salvinorin A Salvia divinorum Drug culture Cannabis culture 420 Cannabis consumption Cannabis cultivation Cannabis edible Cannabis rights Cannabis rights leaders List of cannabis rights organizations Cannabis smoking Cannabis Social Club Cannabis tea Cannabis vaping Head shop Legal history of cannabis in the United States Legality of cannabis Marijuana 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prohibition Cannabis rights Capital punishment for drug trafficking Cognitive liberty Designer drug Drug court Drug possession Drug test Narc Politics of drug abuse War on drugs Mexican drug war Plan Colombia Philippine drug war Zero tolerance Other Drug production and trade Drug production Coca production in Colombia Drug precursors Opium production in Afghanistan Rolling meth lab Government drug experiments MKUltra Edgewood Arsenal human experiments Operation Midnight Climax Drug trade Illegal drug trade Afghanistan Aruba Australia Bangladesh Belize Benin Bhutan Bolivia Brazil Burma Cambodia Chile China Colombia Costa Rica Cuba Cyprus Dominican Republic El Salvador Estonia Finland Germany Haiti Honduras India Indian Ocean region Iran Italy Japan Kenya Kosovo Kyrgyzstan Laos Latin America Latvia Malaysia Mauritius Moldova Nigeria Norway Oman Panama Papua New Guinea Paraguay Philippines Poland Portugal Puerto Rico Russia Saint Kitts and Nevis Seychelles Slovakia South Africa South 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v t e Stimulants Adamantanes Adapromine Amantadine Bromantane Memantine Rimantadine Adenosine antagonists 8-Chlorotheophylline 8-Cyclopentyltheophylline 8-Phenyltheophylline Aminophylline Caffeine CGS-15943 Dimethazan Istradefylline Paraxanthine SCH-58261 Theobromine Theophylline Alkylamines Cyclopentamine Cypenamine Cyprodenate Heptaminol Isometheptene Methylhexaneamine Octodrine Propylhexedrine Tuaminoheptane Ampakines CX-516 CX-546 CX-614 CX-691 CX-717 IDRA-21 LY-404,187 LY-503,430 Nooglutyl Org 26576 PEPA S-18986 Sunifiram Unifiram Arylcyclohexylamines Benocyclidine Dieticyclidine Esketamine Eticyclidine Gacyclidine Ketamine Phencyclamine Phencyclidine Rolicyclidine Tenocyclidine Tiletamine Benzazepines 6-Br-APB SKF-77434 SKF-81297 SKF-82958 Cathinones 3-FMC 3-MMC 3,4-DMMC 4-BMC 4-CMC 4-Methylbuphedrone 4-Methylcathinone 4-MEAP 4-Methylpentedrone Amfepramone Benzedrone Buphedrone Bupropion Butylone Cathinone Dimethylcathinone Ethcathinone Ethylone Flephedrone Hexedrone Isoethcathinone Mephedrone Methcathinone Methedrone Methylenedioxycathinone Methylone Mexedrone N-Ethylbuphedrone N-Ethylhexedrone Pentedrone Pentylone Phthalimidopropiophenone Cholinergics A-84,543 A-366,833 ABT-202 ABT-418 AR-R17779 Altinicline Anabasine Arecoline Bradanicline Cotinine Cytisine Dianicline Epibatidine Epiboxidine GTS-21 Ispronicline Nicotine PHA-543,613 PNU-120,596 PNU-282,987 Pozanicline Rivanicline Sazetidine A SIB-1553A SSR-180,711 TC-1698 TC-1827 TC-2216 Tebanicline UB-165 Varenicline WAY-317,538 Convulsants Anatoxin-a Bicuculline DMCM Flurothyl Gabazine Pentetrazol Picrotoxin Strychnine Thujone Eugeroics Adrafinil Armodafinil CRL-40,940 CRL-40,941 Fluorenol Modafinil Oxazolines 4-Methylaminorex Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone Phenethylamines 1-(4-Methylphenyl)-2-aminobutane 1-Methylamino-1-(3,4-methylenedioxyphenyl)propane 2-Fluoroamphetamine 2-Fluoromethamphetamine 2-OH-PEA 2-Phenyl-3-aminobutane 2,3-MDA 3-Fluoroamphetamine 3-Fluoroethamphetamine 3-Methoxyamphetamine 3-Methylamphetamine 4-Fluoroamphetamine 4-Fluoromethamphetamine 4-MA 4-ME 4-MMA 4-MTA 6-FNE AL-1095 Alfetamine a-Ethylphenethylamine Amfecloral Amfepentorex Amidephrine 2-Amino-1,2-dihydronaphthalene 2-Aminoindane 5-(2-Aminopropyl)indole 2-Aminotetralin Acridorex Amphetamine (Dextroamphetamine, Levoamphetamine) Amphetaminil Arbutamine β-Methylphenethylamine β-Phenylmethamphetamine Benfluorex Benzphetamine BDB BOH 3-Benzhydrylmorpholine BPAP Camfetamine Cathine Chlorphentermine Cilobamine Cinnamedrine Clenbuterol Clobenzorex Cloforex Clortermine Cypenamine D-Deprenyl Denopamine Dimethoxyamphetamine Dimethylamphetamine Dobutamine DOPA (Dextrodopa, Levodopa) Dopamine Dopexamine Droxidopa EBDB Ephedrine Epinephrine Epinine Etafedrine Ethylnorepinephrine Etilamfetamine Etilefrine Famprofazone Fencamfamin Fencamine Fenethylline Fenfluramine (Dexfenfluramine, Levofenfluramine) Fenproporex Feprosidnine FDE Fludorex 4-Fluorodeprenyl Formetorex Furfenorex Gepefrine Hexapradol HMMA Hordenine 4-Hydroxyamphetamine 5-Iodo-2-aminoindane Ibopamine Indanylamphetamine Iofetamine Isoetarine Isoprenaline L-Deprenyl (Selegiline) Lefetamine Lisdexamfetamine Lomardexamfetamine Lophophine MBDB MDA (tenamfetamine) MDBU MDEA MDMA (midomafetamine) MDMPEA MDOH MDPR MDPEA Mefenorex Mephentermine Metanephrine Metaraminol Mesocarb Methamphetamine (Dextromethamphetamine, Levomethamphetamine) Methoxamine Methoxyphenamine MMA Methoxyphenamine MMDA MMDMA MMMA Morforex N,alpha-Diethylphenylethylamine N,N-Dimethylphenethylamine Naphthylamphetamine Nisoxetine Norepinephrine Norfenefrine Norfenfluramine Normetanephrine L-Norpseudoephedrine Octopamine Orciprenaline Ortetamine Oxifentorex Oxilofrine PBA PCA PCMA PHA Pentorex Phenatine Phenpromethamine Phentermine Phenylalanine Phenylephrine Phenylpropanolamine Pholedrine PIA PMA PMEA PMMA PPAP Prenylamine Propylamphetamine Pseudoephedrine Pyr-AI Ropinirole Salbutamol (Levosalbutamol) Sibutramine Solriamfetol Synephrine Theodrenaline Tiflorex Tranylcypromine Tyramine Tyrosine Xylopropamine Zylofuramine Phenylmorpholines 3-Fluorophenmetrazine Fenbutrazate Fenmetramide G-130 Manifaxine Morazone Morforex Oxaflozane PD-128,907 Phendimetrazine Phenmetrazine 2-Phenyl-3,6-dimethylmorpholine Pseudophenmetrazine Radafaxine Piperazines 2C-B-BZP 3C-PEP BZP CM156 DBL-583 GBR-12783 GBR-12935 GBR-13069 GBR-13098 GBR-13119 JJC8-088 MeOPP MBZP oMPP Vanoxerine Piperidines 1-Benzyl-4-(2-(diphenylmethoxy)ethyl)piperidine 2-Benzylpiperidine 2-Methyl-3-phenylpiperidine 3,4-Dichloromethylphenidate 4-Benzylpiperidine 4-Fluoromethylphenidate 4-Methylmethylphenidate Desoxypipradrol Difemetorex Diphenylpyraline Ethylnaphthidate Ethylphenidate Methylnaphthidate Isopropylphenidate JZ-IV-10 Methylphenidate (Dexmethylphenidate) Nocaine Phacetoperane Pipradrol Propylphenidate Serdexmethylphenidate SCH-5472 Phenethylpyrrolidines 2-Diphenylmethylpyrrolidine 4-Cl-PVP 5-DBFPV α-PPP α-PBP α-PCYP α-PHiP α-PHP α-PHPP α-PVP α-PVT Diphenylprolinol DMPVP FPOP FPVP MDPPP MDPBP MPBP MPEP MPHP MPPP MOPVP MOPPP Indapyrophenidone MDPV Naphyrone PEP Picilorex Prolintane Pyrovalerone Racetams Oxiracetam Phenylpiracetam Phenylpiracetam hydrazide Psychedelics 2,5-DMA (DOH) 2C-B 2C-D 2C-G-N 5-MeO-DiPT 5-MeO-MiPT Ariadne (4C-DOM; BL-3912; Dimoxamine) ASR-2001 (2CB-5PrO) DOET DOM DON DOPR LSD MTFEM Tropanes 4-fluorotropacocaine 4'-Fluorococaine Altropane (IACFT) Brasofensine CFT (WIN 35,428) β-CIT (RTI-55) Cocaethylene Cocaine Dichloropane (RTI-111) Difluoropine FE-β-CPPIT FP-β-CPPIT Ioflupane (123I) Norcocaine PIT PTT RTI-31 RTI-32 RTI-51 RTI-112 RTI-113 RTI-120 RTI-121 (IPCIT) RTI-126 RTI-150 RTI-177 RTI-229 RTI-336 RTI-354 RTI-371 RTI-386 Salicylmethylecgonine Tesofensine Troparil (β-CPT, WIN 35,065-2) Tropoxane WF-23 WF-33 Tryptamines 4-HO-αMT 4-Methyl-αET 4-Methyl-αMT 5-Chloro-αMT 5-Fluoro-αMT 5-MeO-αET 5-MeO-αMT 5-MeO-DIPT 6-Fluoro-αMT 7-Methyl-αET αET αMT Others 2-MDP 3,3-Diphenylcyclobutanamine Amfonelic acid Amineptine Amiphenazole Atipamezole Atomoxetine Bemegride Benzydamine BTQ BTS 74,398 Centanafadine Ciclazindol Clofenciclan Cropropamide Crotetamide D-161 Desipramine Diclofensine Dimethocaine Efaroxan Etamivan Fenisorex Fenpentadiol Gamfexine Gilutensin GSK1360707F GYKI-52895 Hexacyclonate Idazoxan Indanorex Indatraline JNJ-7925476 Lazabemide Leptacline Lomevactone LR-5182 Mazindol Meclofenoxate Medifoxamine Mefexamide Methamnetamine Methastyridone Methiopropamine Naphthylaminopropane Nefopam Nikethamide Nomifensine O-2172 Oxaprotiline PNU-99,194 PRC200-SS Rasagiline Rauwolscine Rubidium chloride Setazindol Tametraline Tandamine Thiopropamine Thiothinone Trazium UH-232 Yohimbine ATC code: N06B

v t e ADHD medications CNSTooltip central nervous system stimulants Amphetamine (Mixed amphetamine salts, Levoamphetamine, Dextroamphetamine, Lisdexamfetamine) Methamphetamine Methylphenidate Dexmethylphenidate Serdexmethylphenidate (+dexmethylphenidate) Non-classical CNS stimulants Armodafinil Atomoxetine Modafinil Viloxazine α2-adrenoceptor agonists Clonidine Guanfacine Antidepressants Amitriptyline Bupropion Buspirone Desipramine Duloxetine Imipramine Milnacipran Moclobemide Nortriptyline Reboxetine Venlafaxine Miscellaneous/others Amantadine Carbamazepine Related articles Attention deficit hyperactivity disorder (ADHD) Attention deficit hyperactivity disorder management Hypokalemic sensory overstimulation Monoamine releasing agent Dopamine (DA) Dopamine transporter (DAT) Dopamine reuptake inhibitor (DRI) Norepinephrine (NE) Norepinephrine transporter (NET) Norepinephrine reuptake inhibitor (NRI) Serotonin (5-HT) Serotonin transporter (SERT) Selective serotonin reuptake inhibitor (SSRI) Serotonin-norepinephrine reuptake inhibitor (SNRI) Norepinephrine-dopamine reuptake inhibitor (NDRI) Serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI)

v t e Wakefulness-promoting agents Catecholaminergic agents Dopamine reuptake inhibitors (DRIs): Adrafinil‡ Armodafinil Esmodafinil Mesocarb‡ Modafinil Phenylpiracetam (fonturacetam) Norepinephrine reuptake inhibitors (NRIs): Atomoxetine Desipramine Reboxetine Viloxazine Norepinephrine–dopamine reuptake inhibitors (NDRIs): Amineptine‡ Bupropion Dexmethylphenidate Methylphenidate Nomifensine‡ Serdexmethylphenidate Solriamfetol Serotonin–norepinephrine–dopamine reuptake inhibitors (SNDRIs): Mazindol Norepinephrine releasing agents (NRAs): Ephedrine Pseudoephedrine Selegiline (via metabolites) Norepinephrine–dopamine releasing agents (NDRAs): Amphetamine Dextroamphetamine Levoamphetamine‡ Lisdexamfetamine Methamphetamine Mixed amphetamine salts Pemoline‡ Orexin receptor agonists Alixorexton§ Balumorexton§ Cleminorexton§ Danavorexton§ Firazorexton§ Ledasorexton§ Oveporexton† Histamine H3 receptor antagonists Pitolisant Samelisant§ Adenosine receptor antagonists Caffeine Istradefylline Paraxanthine Others GABAA receptor antagonists and negative allosteric modulators (e.g., clarithromycin, flumazenil, pentylenetetrazol (pentetrazol)) GABAB receptor agonists (e.g., sodium oxybate/γ-hydroxybutyrate (GHB)) (via improved nightly sleep) Nicotinic acetylcholine receptor agonists (e.g., nicotine) #WHO-EM ‡Withdrawn from market Clinical trials: †Phase III §Never to phase III See also: Stimulants List of investigational narcolepsy and hypersomnia drugs

Pharmacodynamics v t e Monoamine releasing agents DRAsTooltip Dopamine releasing agents Morpholines: Fenbutrazate Fenmetramide Morazone Morforex Phendimetrazine Phenmetrazine Pseudophenmetrazine Oxazolines: 4-MAR Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone Phenethylamines: 2-OH-PEA 4-CAB 4-FA 4-FMA 4-MA 4-MMA 5-APB 5-APBT 5-MAPB 6-APB 6-APBT 6-MAPB Alfetamine Amfecloral Amfepentorex Amfepramone Amphetamine (Dextroamphetamine Levoamphetamine) Amphetaminil β-Me-PEA BDB BOH Benzphetamine Buphedrone Butylone Cathine Cathinone Clobenzorex Clortermine D-Deprenyl DMA DMMA Dimethylamphetamine Ephedrine Ethcathinone EBDB Ethylone Etilamfetamine Famprofazone Fenethylline Fenproporex Flephedrone Fludorex 4-Fluorodeprenyl Furfenorex Hordenine 4-Hydroxyamphetamine Iofetamine (123I) Lisdexamfetamine Lomardexamfetamine Lophophine Mefenorex Mephedrone Metamfepramone Methamphetamine Dextromethamphetamine Levomethamphetamine Methcathinone Methedrone MMDA MMDMA MBDB MDA (tenamfetamine) MDEA MDMA (midomafetamine) MDMPEA MDOH MDPEA Methylone Morforex Ortetamine pBA pCA pIA Pholedrine Phenethylamine Pholedrine Phenpromethamine Prenylamine Propylamphetamine Pseudoephedrine SDA (3T-MDA) SDMA (3T-MDMA) Tiflorex Tyramine Xylopropamine Zylofuramine Piperazines: 2C-B-BZP BZP MBZP MDBZP MeOPP oMPP Others: 2-ADN 2-AI 2-AT 4-BP 5-APDI 5-IAI Amineptine Clofenciclan Cyclopentamine Cypenamine Cyprodenate Feprosidnine Gilutensin Heptaminol Hexacyclonate Indanorex Isometheptene Methylhexanamine Naphthylaminopropane Octodrine Phthalimidopropiophenone Phenylbiguanide Propylhexedrine NRAsTooltip Norepinephrine releasing agents Morpholines: Fenbutrazate Fenmetramide Morazone Morforex Phendimetrazine Phenmetrazine Pseudophenmetrazine Oxazolines: 4-MAR Aminorex Clominorex Cyclazodone Fenozolone Fluminorex Pemoline Thozalinone Phenethylamines: 2-OH-PEA 4-CAB 4-FA 4-FMA 4-MA 4-MMA 4-ME 5-APB 5-APBT 5-MAPB 6-APB 6-APBT 6-MAPB Alfetamine Amfecloral Amfepentorex Amfepramone Amphetamine Dextroamphetamine Levoamphetamine Amphetaminil β-Me-PEA BDB Benzphetamine BOH Buphedrone Butylone Cathine Cathinone Clobenzorex Clortermine Deprenyl Dimethylamphetamine DMA DMMA EBDB Ephedrine Ethcathinone Ethylone Etilamfetamine Famprofazone Fenethylline Fenproporex Flephedrone Fludorex 4-Fluorodeprenyl Furfenorex Hordenine 4-Hydroxyamphetamine 5-APDI (IAP) Iofetamine (123I) Lisdexamfetamine Lomardexamfetamine Lophophine MBDB MDA (tenamfetamine) MDEA MDMA (midomafetamine) Metamfepramone MDMPEA MDOH MDPEA Mefenorex Mephedrone Mephentermine Methamphetamine Dextromethamphetamine Levomethamphetamine Methcathinone Methedrone Methylone Morforex Naphthylaminopropane Ortetamine pBA pCA Pentorex Phenethylamine Pholedrine Phenpromethamine Phentermine Phenylpropanolamine pIA Prenylamine Propylamphetamine Pseudoephedrine SDA (3T-MDA) SDMA (3T-MDMA) Selegiline (also D-Deprenyl) Tiflorex Tyramine Xylopropamine Zylofuramine Piperazines: 2C-B-BZP BZP MBZP mCPP MDBZP MeOPP oMPP pFPP Others: 2-ADN 2-AI 2-AT 2-BP 4-BP 5-IAI Clofenciclan Cyclopentamine Cypenamine Cyprodenate Feprosidnine Gilutensin Heptaminol Hexacyclonate Indanorex Isometheptene Methylhexanamine Octodrine Phthalimidopropiophenone Propylhexedrine Tuaminoheptane SRAsTooltip Serotonin releasing agents Aminoindanes: 5-IAI AMMI ETAI MDAI MDMAI MMAI TAI Aminotetralins: 6-CAT 8-OH-DPAT MDAT MDMAT Oxazolines: 4-Methylaminorex Aminorex Clominorex Fluminorex Phenethylamines: 2-Methyl-MDA pCPE 4-CAB 4-FA 4-FMA 4-HA 4-MTA 4-ME 5-APB 5-APBT 5-APDB 5-MAPB 5-Methyl-MDA 6-APB 6-APBT 6-APDB 6-MAPB 6-Methyl-MDA AEMMA Amiflamine BDB BOH Brephedrone Butylone Chlorphentermine Cloforex Amfepramone Metamfepramone DCA Dexfenfluramine DFMDA DMA DMMA EBDB EDMA Ethylone Etolorex Fenfluramine Flephedrone Flucetorex IAP Iofetamine Levofenfluramine Lophophine MBDB MDA (tenamfetamine) MDEA MDHMA MDMA (midomafetamine) MDMPEA MDOH MDPEA Mephedrone Methedrone Methylone MMA MMDA MMDA-3b MMDMA MMMA NAP Norfenfluramine 4-TFMA pBA pCA pIA PMA PMEA PMMA SDA (3T-MDA) SDMA (3T-MDMA) TAP Piperazines: 2C-B-BZP 3-MeOPP BZP DCPP MBZP mCPP MDBZP MeOPP Mepiprazole oMPP pCPP pFPP pTFMPP TFMPP Tryptamines: 4-Methyl-αET 4-Methyl-αMT 5-CT 5-MeO-αET 5-MeO-αMT 5-MT αET αMT DMT Tryptamine Others/unsorted: Indeloxazine PAL-335 Viqualine Others DAT modulators: Agonist-like: SoRI-9804 SoRI-20040; Antagonist-like: SoRI-20041 Adrenergic release blockers: Bethanidine Bretylium Guanadrel Guanazodine Guanethidine Guanoxan See also: Receptor/signaling modulators • Monoamine reuptake inhibitors • Adrenergics • Dopaminergics • Serotonergics • Monoamine metabolism modulators • Monoamine neurotoxins v t e Trace amine-associated receptor modulators TAAR1Tooltip Trace amine-associated receptor 1 Agonists Endogenous Monoamine neurotransmitters Dopamine Histamine Epinephrine (adrenaline) Norepinephrine (noradrenaline) Serotonin Trace amines 3-Iodothyronamine 3-Methoxytyramine N-Methylphenethylamine N-Methyltyramine m-Octopamine p-Octopamine β-Phenethylamine Phenylethanolamine Synephrine Tryptamine m-Tyramine p-Tyramine Others Cyclohexylamine Isoamylamine Trimethylamine Exogenous 2C-B 2C-B-Fly 2C-E 2C-H 2C-P 2C-T-7 A-77636 2-Aminoindane Amphetamine AP163 Apomorphine Asenapine Bromocriptine Cathinone Chlorpromazine Clonidine Cyproheptadine Dihydroergotamine Dimethyltryptamine DOB DOET DOI DOM N,N-Dimethylphenethylamine Ergometrine Fenoldopam Fenoterol 4-Fluoroamphetamine Guanabenz Guanfacine Halostachine Higenamine Hordenine 4-Hydroxyamphetamine (norpholedrine) Idazoxan 5-Iodo-2-aminoindane Isoprenaline Isopropyloctopamine Lisuride LK00764 LSD LY03020 MDA (tenamfetamine) MDAI MDMA (midomafetamine) Mescaline Metergoline N-Methyl-2-AI 2-Methylphenethylamine 3-Methylphenethylamine 4-Methylphenethylamine β-Methylphenethylamine Methamphetamine MMA MPTP Naphazoline Nomifensine Norfenfluramine Oxymetazoline Phentermine Phentolamine o-PIT Psilocin Ralmitaront (RG-7906, RO6889450) RG-7351 RG-7410 RO5073012 RO5166017 RO5203648 RO5256390 RO5263397 S18616 Selegiline (L-deprenyl) Selutaront Solriamfetol Tolazoline Ulotaront (SEP-363856) Antagonists Compound 22 EPPTB (RO-5212773) RTI-7470-44 Inverse agonists EPPTB (RO-5212773) TAAR5Tooltip Trace amine-associated receptor 5 Agonists N,N-Dimethylethylamine Trimethylamine Inverse agonists 3-Iodothyronamine Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as the List of trace amines, TAAR, and TAAR1 pages. See also: Receptor/signaling modulators v t e Sigma receptor modulators σ1 Agonists: 3-PPP 4-PPBP 5-MeO-DMT Alazocine (SKF-10047) Amantadine ANAVEX 1-41 ANAVEX 3-71 (AF710B) Arketamine BD-737 BD-1052 Blarcamesine (ANAVEX 2-73) Captodiame Citalopram CGRPTooltip Calcitonin gene-related peptide Cloperastine Cocaine Cutamesine (SA-4503) Cyclazocine Dehydroepiandrosterone (DHEA) (prasterone) Dehydroepiandrosterone sulfate (DHEA-S) (prasterone sulfate) Dextrallorphan Dextromethorphan (DXM) Dextrorphan (DXO) Dimemorfan Dimethyltryptamine (DMT) Ditolylguanidine (DTG) Donepezil Eliprodil Escitalopram Fabomotizole (afobazole) Fluoxetine Fluvoxamine Ifenprodil Igmesine (JO-1784) IPAB Ketamine L-687384 MDMA (midomafetamine) Memantine Methamphetamine Methoxetamine Methylphenidate Nepinalone Neuropeptide Y Noscapine OPC-14523 Opipramol Pentazocine Pentoxyverine (carbetapentane) PRE-084 Pregnenolone Pregnenolone sulfate Pridopidine Racemethorphan (methorphan) Racemorphan (morphanol) UMB-23 UMB-82 Antagonists: 3-PPP AC-927 BD-1008 BD-1031 BD-1047 BD-1060 BD-1063 BD-1067 BMY-14802 (BMS-181100) CM-156 Dup-734 E-5842 E-52862 (S1RA) Haloperidol LR-132 LR-172 MS-377 NE-100 NPC-16377 Panamesine (EMD-57455) PD-144418 Pentazocine Progesterone Rimcazole (BW-234U) Sertraline SR-31742A Allosteric modulators: Phenytoin; Positive: Methylphenylpiracetam SOMCL-668 Unknown/unsorted: 3-Methoxydextrallorphan 3-MeO-PCP 4C-T-2 4-IBP 4-IPBS 4-MeO-PCP 5-MeO-DALT 5-MeO-DiPT Amitriptyline Azidopamil Chlorpromazine Clemastine Clomipramine Clorgiline D-Deprenyl DiPTTooltip N,N-Diisopropyltryptamine DPTTooltip N,N-Dipropyltryptamine Ibogaine Imipramine KCR-12-83.1 Nemonapride Noribogaine RHL-033 RS-67,333 RTI-55 Saffron Safinamide Selegiline Spipethiane Trifluoperazine W-18 YKP10A σ2 Agonists: 3-PPP Arketamine BD-1047 BD1063 Ditolylguanidine (DTG) DKR-1005 DKR-1051 Haloperidol Ifenprodil Ketamine MDMA (midomafetamine) Methamphetamine OPC-14523 Opipramol PB-28 Phencyclidine Siramesine (Lu 28-179) UKH-1114 Antagonists: AC-927 BD-1008 BD-1067 CM-156 LR-172 MIN-101 Panamesine (EMD-57455) SAS-0132 Zervimesine (CT-1812) Unknown/unsorted: 3-Methoxydextrallorphan 3-MeO-PCE 4-MeO-PCP 5-MeO-DALT 5-MeO-DiPT Clemastine DiPTTooltip N,N-Diisopropyltryptamine DPTTooltip N,N-Dipropyltryptamine Ibogaine Lu 29-252 Nemonapride Nepinalone Noribogaine Pentazocine RS-67,333 Safinamide TMATooltip 3,4,5-Trimethoxyamphetamine UMB-23 UMB-82 W-18 Unsorted Agonists: Berberine Ethylketazocine Fourphit Metaphit Naluzotan Tapentadol Tenocyclidine Antagonists: AHD1 AZ66 Lamotrigine Naloxone SM-21 UMB-100 UMB-101 UMB-103 UMB-116 YZ-011 YZ-069 YZ-185 Allosteric modulators: SKF-83959 Unknown/unsorted: 18-Methoxycoronaridine BMY-13980 Butaclamol Caramiphen Carvotroline Chlorphenamine (chlorpheniramine) Chlorpromazine Cinnarizine Cinuperone Clocapramine Dezocine EMD-59983 Hypericin (St. John's wort) Fluphenazine Gevotroline (WY-47384) Mepyramine (pyrilamine) Molindone Perphenazine Pimozide Proadifen Promethazine Propranolol Quinidine Remoxipride SL 82.0715 SR-31747A Tiospirone (BMY-13859) Venlafaxine See also: Receptor/signaling modulators v t e Monoaminergic neurotoxins Dopaminergic 2′-CH3-MPTP (2′-methyl-MPTP) 2,4,5-THA 2,4,5-THMA 4-MMA 5-S-Cysteinyldopamine 5,6-DHT 6-Hydroxydopa 6-OHDA quinone 6,7-DHT ALDH inhibitors (e.g., disulfiram, methylmercury) Amphetamine V-61 Benomyl Daidzin Dieldrin DOPA quinone DOPAL DOPAL quinone Dopamine Dopamine quinone Fenpropathrin Haloperidol HPP+ HPTP Imidazole propionate (ImP) Mancozeb Maneb Mephedrone Methamphetamine Methcathinone Methylone MPP+ (cyperquat) MPTP N-Methylnorsalsolinol Norsalsolinol Oxidopamine (6-OHDA) Paraquat Rotenone Salsolinol TaClo (1-TCMTC) Ziram Noradrenergic 2′-NH2-MPTP (2′-amino-MPTP) 2,4,5-THA 4,5-DHT 5,6-DHT 5,7-DHT 6-Hydroxydopa DOPEGAL DSP-4 MDA (tenamfetamine) Oxidopamine (6-OHDA) Xylamine V-61 Serotonergic 2′-NH2-MPTP (2′-amino-MPTP) 2,4-DCA 2,4,5-THA 2,4,5-THMA pCPE 3-CA 3,4-DCA 4-CAB (α-ethyl-PCA) 4-CMA 4-HO-5-MeO-T 4,5-DHT 5-IAI 5-MAPB 5-MeO-DiPT 5,6-DHT 5,7-DHT 6,7-DHT αET ETAI Fenfluramine Haloperidol HHA (α-methyldopamine) HHMA (α-methylepinine, α,N-dimethyldopamine) HPP+ HPTP MBDB MDA (tenamfetamine) MDMA (midomafetamine) Mephedrone Methamphetamine Methylone Norfenfluramine PBA PBMA PCA PCMA PIA TAI Unsorted 2,5-DDM-DOM 5-HIAL RHPP+ RHPTP See also: Receptor/signaling modulators • Adrenergics • Dopaminergics • Melatonergics • Serotonergics • Monoamine reuptake inhibitors • Monoamine releasing agents • Monoamine metabolism modulators

v t e Phenethylamines Phenethylamines Psychedelics: 3,4-DMPEA-NDEPA 24H-NBOMe 25B-NBOMe 25C-NBOMe 25D-NBOMe 25D-NM-NDEAOP 25H-NBOMe 25I-NBOMe 25N-NBOMe 25O-NBOMe 2C-B 2C-B-AN 2C-B-OH 2C-Bn 2C-Bu 2C-C 2C-CN 2C-CP 2C-D 2C-DB 2C-E 2C-EF 2C-F 2C-G 2C-G-2 2C-G-3 2C-G-4 2C-G-5 2C-G-6 2C-G-N 2C-H 2C-I 2C-iBu 2C-iP 2C-N 2C-NH2 2C-O 2C-O-2 2C-O-4 2C-P 2C-Ph 2C-Se 2C-Se-TFM 2C-T 2C-T-2 2C-T-3 2C-T-4 2C-T-5 2C-T-6 2C-T-7 2C-T-8 2C-T-9 2C-T-10 2C-T-11 2C-T-12 2C-T-13 2C-T-14 2C-T-15 2C-T-16 2C-T-17 2C-T-18 2C-T-19 2C-T-20 2C-T-21 2C-T-21.5 2C-T-22 2C-T-23 2C-T-24 2C-T-25 2C-T-27 2C-T-28 2C-T-30 2C-T-31 2C-T-32 2C-T-33 2C-tBu 2C-Te 2C-TFE 2C-TFM 2C-YN 2C-V Allylescaline BOH-2C-B CT-5172 DESOXY N,N-Diformylmescaline Escaline N-Formylmescaline Isoproscaline 3-Methoxy-4,5-dihydroxyphenethylamine M-NDEPA Macromerine MEPEA Mescaline Metaescaline Methallylescaline N-DEAOP-NMPEA N-Methylmescaline Proscaline Psi-2C-T-4 Trichocereine (N,N-dimethylmescaline) Stimulants: Phenylethanolamine Hordenine Phenethylamine Phenpromethamine α-Methylphenethylamine (amphetamine) β-Methylphenethylamine m-Methylphenethylamine N-Methylphenethylamine o-Methylphenethylamine p-Methylphenethylamine Phenacylamine (β-ketophenethylamine) Solriamfetol Entactogens: Lophophine MDPEA MDMPEA Others: N-Acetylmescaline Amidephrine ASR-2001 Biscaline BOH Buscaline Denopamine Desvenlafaxine DMPEA F-17475 Mescaloruvic acid Mescaloxylic acid Phenibut 4-PhPr-PEA pCPE Pronethalol Salbutamol Levosalbutamol Venlafaxine Amphetamines Psychedelics: 3C-AL 3C-BZ 3C-E 3C-MAL 3C-P Aleph Beatrice Bromo-DragonFLY DMA DMMDA DOB DOB-NDEPA DOC DODB DOEF DOET DOI DOI-NDEPA DOM DOM-NDEPA DON DOPR DOTFM DOTFM-NDEPA DOTMA Ganesha MMDA MMDA-2 MMDA-3a MMDA-3b N-Hydroxy-DOM Psi-DOM TMA TMA-2 TMA-2-NDEPA TeMA ZDCM-04 Stimulants: 2-FA 2-FMA 3-FA 3-FMA β-Phenylmethamphetamine Acridorex Alfetamine Amfecloral Amfepentorex Amphetamine Dextroamphetamine Levoamphetamine Amphetaminil Benfluorex Benzphetamine Cathine Clobenzorex Deprenyl D-Deprenyl Dimethylamphetamine Ephedrine FDE Ephenidine Etafedrine Etilamfetamine Famprofazone Fencamfamin Fencamine Fenethylline Fenfluramine Dexfenfluramine Levofenfluramine Fenproporex Flucetorex Fludorex 4-Fluorodeprenyl Formetorex Furfenorex Gepefrine 4-Hydroxyamphetamine 4-ME Iofetamine Isopropylamphetamine Lefetamine Lisdexamfetamine Lomardexamfetamine Mefenorex Metaraminol Methamphetamine Dextromethamphetamine Levomethamphetamine Methoxamine Methoxyphenamine MMA Morforex Norfenfluramine L-Norpseudoephedrine α,N-Diethylphenylethylamine Oxifentorex Oxilofrine Ortetamine PBA PBMA PCA PCMA PFA PFMA PIA PIMA PMA PMEA PMMA Phenylpropanolamine Pholedrine Prenylamine Propylamphetamine Pseudoephedrine Sibutramine Tiflorex Xylopropamine Zylofuramine Entactogens: 4-FA 4-FMA 4-MA 4-MMA 4-MTA 5-APB 5-APBT 5-APDB 5-EAPB 5-IT 5-MAPB 5-MAPDB 6-APB 6-APDB 6-APBT 6-Chloro-MDMA 6-EAPB 6-IT 6-MAPB 6-MAPDB EDA IAP 2,3-MDA 3,4-MDA (tenamfetamine) MDEA MDHMA MDMA (midomafetamine) MDOH Methamnetamine MMDMA Naphthylaminopropane ODMA SDA (3T-MDA) SDMA (3T-MDMA) SeDMA TAP TDMA Others: 3,4-DCA DOOH Amiflamine Cafedrine Deprenyl D-Deprenyl Selegiline (L-deprenyl) DiFMDA 4-Fluorodeprenyl 4-Fluoroselegiline Thiamphenicol UWA-101 (α-cPr-MDMA) Phentermines Stimulants: Chlorphentermine Cloforex Clortermine Etolorex Mephentermine Pentorex Phentermine Entactogens: MDPH MDMPH Others: Cericlamine Cathinones Stimulants: 3-BMC 3-CMC 3-FMC 4-MC 4-BMC 4-CMC 4-EMC 4-FMC 4-MEC 4-MeMABP 4-MPD Amfepramone Benzedrone Brephedrone Buphedrone Bupropion Cathinone Dimethylcathinone Ethcathinone Eutylone Hydroxybupropion Methcathinone Methedrone NEB N-Ethylhexedrone N-Ethylpentedrone Pentedrone Pentylone Entactogens: 3,4-DMMC 3-MMC Butylone Ethylone Methylone Methylenedioxycathinone Mephedrone Propylone Phenylisobutylamines (and further-extended) Entactogens: 4-CAB 4-MAB Ariadne BDB Butylone EBDB Eutylone MBDB Stimulants: α-Propylphenethylamine Hexapradol Phenylisobutylamine (α-ethylphenethylamine) Catecholamines (and close relatives) 6-FNE 6-OHDA α-Me-DA α-Me-TRA A-69024 Adrenochrome Arbutamine Ciladopa D-DOPA (dextrodopa) Dimetofrine Dipropyldopamine (DPDA) Dobutamine Dopamine Dopexamine Epinephrine (adrenaline) Epinine Etilefrine Ethylnorepinephrine Fenclonine Ibopamine Isoprenaline Isoetarine L-DOPA (levodopa) L-DOPS (droxidopa) L-Phenylalanine L-Tyrosine m-Tyramine Metanephrine Metaraminol Metaterol Metirosine Methyldopa N,N-Dimethyldopamine Nordefrin Levonordefrin Norepinephrine (noradrenaline) Norfenefrine (m-octopamine) Normetanephrine Orciprenaline p-Octopamine p-Tyramine Phenylephrine Synephrine Theodrenaline Cyclized phenethylamines Phenylalkylpyrrolidines α-PBP α-PHP α-PPP α-PVP MDPBP MDPPP MDPV 4-MePBP 4-MePHP 4-MePPP Fluorolintane MOPPP MOPVP MPBP MPEP MPHP MPPP Naphyrone PEP Prolintane Pyrovalerone 2-Benzylpiperidines (phenidates) 2-Benzylpiperidine 3-Bromomethylphenidate 3-Chloromethylphenidate 3-Methylmethylphenidate 3,4-Dichloro-2-benzylpiperidine 3,4-Dichloroethylphenidate 3,4-Dichloromethylphenidate 4-Bromoethylphenidate 4-Bromomethylphenidate 4-Chloromethylphenidate 4-Fluoroethylphenidate 4-Fluoroisopropylphenidate 4-Fluoromethylphenidate 4-Methyl-2-benzylpiperidine 4-Methylisopropylphenidate 4-Methylmethylphenidate 4-Nitromethylphenidate α-Acetyl-2-benzylpiperidine α-Keto-2-benzylpiperidine CPMBP DMBMPP Desoxypipradrol (2-DPMP) Difemetorex Ethylnaphthidate (HDEP-28) Ethylphenidate Isopropylnaphthidate Isopropylphenidate MDMPH Methylnaphthidate (HDMP-28) Methylphenidate Phacetoperane Pipradrol Propylphenidate Rimiterol Ritalinamide Ritalinic acid SCH-5472 Serdexmethylphenidate Phenylmorpholines (phenmetrazines) (2R,3R)-Hydroxybupropion 2-(2,5-Dimethoxy-4-bromophenyl)morpholine 2-Fluorophenmetrazine 2-Methylphenmetrazine 2-Phenylmorpholine 2-Phenyl-3,6-dimethylmorpholine 3-Chlorophenmetrazine (PAL-594) 3-Fluorophenetrazine 3-Fluorophenmetrazine (PAL-593) 3-Methoxyphenmetrazine 3-Methylphenmetrazine (PAL-773) 4-Fluorophenmetrazine (PAL-748) 4-Methylphendimetrazine 4-Methylphenmetrazine (PAL-747) 2C-B-morpholine Fenbutrazate Fenmetramide Flumexadol G-130 Isophenmetrazine Manifaxine Methylenedioxyphenmetrazine Morazone N-Ethylphenmetrazol Naphthylmetrazine (PAL-704) Naphthylmorpholine (PAL-678) Oxaflozane PDM-35 PF-219,061) Phendimetrazine Phenetrazine Phenmetetrazine Phenmetrazine Phenmetrazol Pseudophenmetrazine Radafaxine ((2S,3S)-hydroxybupropion) Phenyloxazolamines (aminorexes) 3-Methylaminorex 4-Ethylaminorex (4-EAR) 4'-Fluoroaminorex 4-Methylaminorex (4-MAR) 4,4'-Dimethylaminorex (4,4'-DMAR) 2C-B-aminorex 2F-MAR 4B-MAR 4C-MAR 4F-MAR Aminorex Clominorex Cyclazodone Ephedroxane Fenozolone Fluminorex MDMAR Methylenedioxyaminorex (MDAR) N-Methylcyclazodone N,N-Dimethylaminorex Pemoline Thozalinone Isoquinolines and tetrahydroisoquinolines A-69024 Anhalamine Anhalidine Anhalinine Anhalonidine Anhalonine Anhalotine Arizonine Calycotomine Carnegine (pectenine) Corypalline Debrisoquine Deglucopterocereine Deutetrabenazine Diclofensine DOB-CR DOM-CR Esproquin Gigantine Hedycarine Heliamine Hydrastinine Hydrocotarnine Hydrohydrastinine (MDMTHIQ; MDMA-CR) Isoanhalamine Isoanhalidine Isoanhalonidine Isocorypalline Isopellotine Isosalsoline Lemaireocereine Longimammamine Longimammatine Longimammidine Longimammosine Lophocerine Lophophorine Lophotine MDMA-CR Mescalotam N-Methylanhalinine N-Methylheliamine N-Methylisosalsoline N-Methyl-DOM-CR (Beatrice-CR) N-Methyl-THIQ (METH-CR) Nomifensine Norsalsolinol Nortehaunine Norweberine O-Methylanhalonidine O-Methylpellotine Pachycereine Pellotine Perafensine Peyoglutam Peyophorine Peyotine PMMA-CR Quinisocaine Reticuline Salsolidine Salsoline Salsolinol TDIQ (MDTHIQ, MDA-CR) Tehaunine Tehaunine N-oxide Tepenine Tetrabenazine Tetrahydroisoquinoline (THIQ; AMPH-CR) Tetrahydropapaveroline Tilisolol Tretoquinol Uberine Valbenazine Weberidine Weberine Zelandopam 2-Aminoindanes 2-Aminoindane (2-AI) 5-IAI Aprindine BFAI BFMAI DHAI DOM-AI ETAI Indantadol MDAI MDMAI MEAI (5-MeO-AI) MMAI NM-2-AI PNU-99,194 Pyr-AI TAI 2-Aminotetralins 2-Aminotetralin (2-AT) 5-OH-DPAT 6-CAT 7-OH-DPAT 8-OH-DPAT AS-19 CHF-1024 DOM-AT MDAT MDMAT Nolomirole UH-232 Others / unsorted 1-Aminomethylindanes (e.g., 2CB-Ind, AMMI, bromojimscaline, jimscaline) 2-ADN 2-Benzhydrylpyrrolidine 2C-B-5-hemiFLY-α6 (BNAP) 2C-B-PYR 2CBecca 2CB7 2CJP 2CLisaB 2CLisaH 3-Aminochromans (e.g., CT-5126, 5-MeO-DPAC, robalzotan, ebalzotan) 3-Benzazepines (e.g., fenoldopam, lorcaserin, 7-chlorolorcaserin, SCHEMBL5334361) 3-Benzhydrylmorpholine 3-Phenylpiperidines (e.g., 3-phenylpiperidine, 3-PPP, OSU-6162 (PNU-96391), LPH-5, LPH-48, 2C-B-3PIP, 2C-B-3PIP-NBOMe, 2C-B-3PIP-POMe, Z3517967757 (Z7757)) 6-AB AL-1095 Aminochromes (e.g., adrenochrome, adrenolutin) AMMT Benzocyclobutenes (e.g., 2CBCB-NBOMe, bromotomscaline, S33005, TCB-2, tomscaline) Benzoxepins (e.g., BBOX, IBOX, TFMBOX) Butyltolylquinuclidine Camfetamine Clausenamide Cypenamine (trans-2-phenylcyclopentylamine) Diphenidine Diphenylprolinol Ergolines (e.g., LSD) Fencamfamin GYKI-52895 HDMP-29 Ivabradine Methoxphenidine Methylmorphenate Milnacipran MT-45 2-Naphthylamine Org 6582 Partial ergolines (e.g., NDTDI, RU-27849, DEIMDHPCA, DEMPDHPCA, DEMPDHPCA-2C-D, RU-27251) PF-592,379 Phenanthrenes (e.g., atherosperminine (atherospermine)) Phenylcyclopropylamines (e.g., DMCPA, TMT, tranylcypromine) Phenylmethylpyrrolidines (e.g., APA-01) Phenylpiracetams (e.g., phenylpiracetam, MRZ-9547, RGPU-95) Pyridopyrroloquinoxalines (e.g., lumateperone, deulumateperone, IHCH-7079, IHCH-7086, IHCH-7113, ITI-1549) Thienopyridines (e.g., SKF-89145, SKF-89615, SKF-89626) Tolazoline Tricyclics (e.g., AMDA, AMDH, benzoctamine, dizocilpine, SpAMDA) ZC-B Related compounds 2-Furylethylamine 2-Pyrrolylethylamine 3-Pyrrolylethylamine 3-Pyrrolylpropylamine 2-Tetrahydrofurylethylamine 4-Benzylpiperidine 7-AB Alkylamines (e.g., 1,3-DMBATooltip 1,3-dimethylbutylamine, 1,4-DMAATooltip 1,4-dimethylamylamine, heptaminol, iproheptine, isometheptene, methylhexanamine/1,3-DMAA, octodrine, oenethyl, tuaminoheptane) Benzylamines (e.g., benzylamine, α-methylbenzylamine, MDM1EA, ALPHA, M-ALPHA, pargyline) Benzylpiperazines (e.g., benzylpiperazine, MDBZP, fipexide) Cyclohexylaminopropanes (e.g., propylhexedrine, norpropylhexedrine) Cyclopentylaminopropanes (e.g., isocyclamine, cyclopentamine) Phenoxyethylamines (e.g., 3,4,5-trimethoxyphenoxyethylamine, CT-4719, ORG-37684) Phenylalkenylamines (e.g., phenylbutenamine) Phenylalkynylamines (e.g., phenylbutynamine) Phenylpiperazines (e.g., 1-phenylpiperazine, mCPPTooltip meta-chlorophenylpiperazine, TFMPPTooltip trifluoromethylphenylpiperazine, oMPPTooltip ortho-methylphenylpiperazine, pFPPTooltip para-fluorophenylpiperazine, pMeOPPTooltip para-methoxyphenylpiperazine) Phenylpropylamines (e.g., phenylpropylamine, homo-MDA, homo-MDMA) Thienylaminopropanes (thiopropamines) (e.g., thiopropamine, methiopropamine, thiothinone) Phenylbutylamines (e.g., 4-Phenylbutylamine, 4-Phenylpentan-1-amine) See also: Tryptamines Ergolines and lysergamides Stimulants Entactogens Psychedelics

Authority control databases International GND FAST National United States France BnF data Spain Israel Other NARA Yale LUX

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Adapted from the Wikipedia article [Methamphetamine](https://en.wikipedia.org/wiki/Methamphetamine) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Methamphetamine?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.