Methamphetamine[note 1] (contracted from N-methylamphetamine) is a potent central nervous

system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-
line treatment for attention deficit hyperactivity disorder and obesity.[17] Methamphetamine was
discovered in 1893 and exists as two enantiomers: levo-methamphetamine and dextro-
methamphetamine.[note 2] Methamphetamine properly refers to a specific chemical, the racemic free
base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure
amine forms. It is rarely prescribed over concerns involving human neurotoxicity and potential for
recreational use as an aphrodisiac and euphoriant, among other concerns, as well as the availability
of safer substitute drugs with comparable treatment efficacy. Dextromethamphetamine is a much
stronger CNS stimulant than levomethamphetamine.
Both methamphetamine and dextromethamphetamine are illicitly trafficked and sold owing to their
potential for recreational use. The highest prevalence of illegal methamphetamine use occurs in
parts of Asia, Oceania, and in the United States, where racemic methamphetamine,
levomethamphetamine, and dextromethamphetamine are classified as schedule II controlled
substances. Levomethamphetamine is available as an over-the-counter (OTC) drug for use as an
inhaled nasal decongestant in the United States.[note 3] Internationally, the production, distribution, sale,
and possession of methamphetamine is restricted or banned in many countries, due to its placement
in schedule II of the United Nations Convention on Psychotropic Substances treaty. While
dextromethamphetamine is a more potent drug, racemic methamphetamine is sometimes illicitly
produced due to the relative ease of synthesis and limited availability of chemical precursors.
In low to moderate doses, methamphetamine can elevate mood, increase alertness, concentration
and energy in fatigued individuals, reduce appetite, and promote weight loss. At relatively high doses,
it can induce psychosis, breakdown of skeletal muscle, seizures and bleeding in the brain. Chronic
high-dose use can precipitate unpredictable and rapid mood swings, stimulant
psychosis (e.g., paranoia, hallucinations, delirium, and delusions) and violent behavior.
Recreationally, methamphetamine's ability to increase energy has been reported to lift
mood and increase sexual desire to such an extent that users are able to engage in sexual activity
continuously for several days.[21] Methamphetamine is known to possess a high addiction liability (i.e.,
a high likelihood that long-term or high dose use will lead to compulsive drug use) and
high dependence liability (i.e. a high likelihood that withdrawalsymptoms will occur when
methamphetamine use ceases). Heavy recreational use of methamphetamine may lead to a post-
acute-withdrawal syndrome, which can persist for months beyond the typical withdrawal period.
Unlike amphetamine, methamphetamine is neurotoxic to human midbrain dopaminergic neurons.[22] It
has also been shown to damage serotonin neurons in the CNS.[23][24]This damage includes adverse
changes in brain structure and function, such as reductions in grey matter volume in several brain
regions and adverse changes in markers of metabolic integrity.[24]
Methamphetamine belongs to the substituted phenethylamine and substituted
amphetamine chemical classes. It is related to the other dimethylphenethylamines as a positional
isomer of these compounds, which share the common chemical formula: C10H15N1.

Medical
In the United States, dextromethamphetamine hydrochloride, under the trade name Desoxyn, has
been approved by the FDA for treating ADHD and obesity in both adults and children;[25][26] however,
the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be
weighed against the inherent risks associated with its use.[25] Methamphetamine is sometimes
prescribed off label for narcolepsy and idiopathic hypersomnia.[27][28] In the United
States, methamphetamine's levorotary form is available in some over-the-counter (OTC) nasal
decongestant products.[note 3]
As methamphetamine is associated with a high potential for misuse, the drug is regulated under
the Controlled Substances Act and is listed under Schedule II in the United
States.[25] Methamphetamine hydrochloride dispensed in the United States is required to include
a boxed warning regarding its potential for recreational misuse and addiction liability.[25]

Recreational
See also: Party and play and the Recreational routes of methamphetamine administration
Methamphetamine is often used recreationally for its effects as a potent euphoriant and stimulant as
well as aphrodisiac qualities.[21]
According to a National Geographic TV documentary on methamphetamine, an entire subculture
known as party and play is based around sexual activity and methamphetamine use.[21] Participants
in this subculture, which consists almost entirely of homosexual male methamphetamine users, will
typically meet up through internet dating sites and have sex.[21] Due to its strong stimulant and
aphrodisiac effects and inhibitory effect on ejaculation, with repeated use, these sexual encounters
will sometimes occur continuously for several days on end.[21] The crash following the use of
methamphetamine in this manner is very often severe, with marked hypersomnia (excessive daytime
sleepiness).[21] The party and play subculture is prevalent in major US cities such as San Francisco
and New York City.[21][29]

Desoxyn tablets – pharmaceutical methamphetamine hydrochloride

Crystal meth – illicit methamphetamine hydrochloride

Contraindications
Methamphetamine is contraindicated in individuals with a history of substance use disorder, heart
disease, or severe agitation or anxiety, or in individuals currently
experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension.[25] The FDA states
that individuals who have experienced hypersensitivity reactions to other stimulants in the past or
are currently taking monoamine oxidase inhibitors should not take methamphetamine.[25] The FDA
also advises individuals with bipolar disorder, depression, elevated blood pressure, liver or kidney
problems, mania, psychosis, Raynaud's phenomenon, seizures, thyroid problems, tics, or Tourette
syndrome to monitor their symptoms while taking methamphetamine.[25] Due to the potential for
stunted growth, the FDA advises monitoring the height and weight of growing children and
adolescents during treatment.[25]

Side effects
Physical
The physical effects of methamphetamine can include loss of appetite, hyperactivity, dilated
pupils, flushed skin, excessive sweating, increased movement, dry mouth and teeth
grinding (leading to "meth mouth"), headache, irregular heartbeat (usually as accelerated
heartbeat or slowed heartbeat), rapid breathing, high blood pressure, low blood pressure, high body
temperature, diarrhea, constipation, blurred vision, dizziness, twitching, numbness, tremors, dry
skin, acne, and pale appearance.[25][30]
Meth mouth
Main article: Meth mouth

A suspected case of meth mouth

Methamphetamine users and addicts may lose their teeth abnormally quickly, regardless of the route
of administration, from a condition informally known as meth mouth.[31] The condition is generally
most severe in users who inject the drug, rather than swallow, smoke, or inhale it.[31] According to
the American Dental Association, meth mouth "is probably caused by a combination of drug-induced
psychological and physiological changes resulting in xerostomia (dry mouth), extended periods of
poor oral hygiene, frequent consumption of high-calorie, carbonated beverages and bruxism (teeth
grinding and clenching)".[31][32] 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.[33]
Sexually transmitted infection
Methamphetamine use was found to be related to higher frequencies of unprotected sexual
intercourse in both HIV-positive and unknown casual partners, an association more pronounced in
HIV-positive participants.[34] 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.[34] Methamphetamine use allows users of both
sexes to engage in prolonged sexual activity, which may cause genital sores and abrasions as well
as priapism in men.[25][35] Methamphetamine may also cause sores and abrasions in the mouth
via bruxism, increasing the risk of sexually transmitted infection.[25][35]
Besides the sexual transmission of HIV, it may also be transmitted between users who share a
common needle.[36] The level of needle sharing among methamphetamine users is similar to that
among other drug injection users.[36]

Psychological
The psychological effects of methamphetamine can include euphoria, dysphoria, changes
in libido, alertness, apprehension and concentration, decreased sense of
fatigue, insomniaor wakefulness, self-confidence, sociability, irritability,
restlessness, grandiosity and repetitive and obsessive behaviors.[25][30][37] Peculiar to
methamphetamine and related stimulants is "punding", persistent non-goal-directed repetitive
activity.[38] Methamphetamine use also has a high association with anxiety, depression, amphetamine
psychosis, suicide, and violent behaviors.[39]

Neurotoxicity and neuroimmune response

This diagram depicts the neuroimmune mechanismsthat mediate methamphetamine-induced

neurodegeneration in the human brain.[40] The NF-κB-mediated neuroimmune response to methamphetamine
use which results in the increased permeability of the blood–brain barrier arises through its binding at and
activation of sigma receptors, the increased production of reactive oxygen species (ROS), reactive nitrogen
species(RNS), and damage-associated molecular pattern molecules (DAMPs), the dysregulation of glutamate
transporters (specifically, EAAT1 and EAAT2) and glucose metabolism, and excessive Ca2+ ion influx in glial
cells and dopamine neurons.[40][41][42]

Unlike amphetamine, methamphetamine is directly neurotoxic to dopamine neurons in both lab

animals and humans.[22][23][24] Moreover, methamphetamine neurotoxicity is associated with an
increased risk of Parkinson's disease, an effect which partially arises through excessive cytosolic
and synaptic production of reactive oxygen species and autoxidation of dopamine.[43][44][45][46][47] In
addition to dopaminergic neurotoxicity, a review of evidence in humans also indicated that high-dose
methamphetamine use can be neurotoxic to serotonin neurons.[24] It has been demonstrated that a
high core temperature is correlated with an increase in the neurotoxic effects of
methamphetamine.[48] As a result of methamphetamine-induced neurotoxicity to dopamine neurons,
chronic use may also lead to post-acute withdrawal which persists months beyond the typical
withdrawal period.[44]
Magnetic resonance imaging studies on human methamphetamine users have also found evidence
of neurodegeneration, or adverse neuroplastic changes in brain structure and function.[24] In
particular, methamphetamine appears to cause hyperintensity and hypertrophy of white matter,
marked shrinkage of hippocampi, and reduced gray matter in the cingulate cortex, limbic cortex,
and paralimbic cortex in recreational methamphetamine users.[24] Moreover, evidence suggests that
adverse changes in the level of biomarkers of metabolic integrity and synthesis occur in recreational
users, such as a reduction in N-acetylaspartate and creatine levels and elevated levels
of choline and myoinositol.[24]
Methamphetamine has been shown to activate TAAR1 in human astrocytes and generate cAMP as
a result.[49] Activation of astrocyte-localized TAAR1 appears to function as a mechanism by which
methamphetamine attenuates membrane-bound EAAT2 (SLC1A2) levels and function in these
cells.[49]
Methamphetamine binds to and activates both sigma receptor subtypes, σ1 and σ2, in the
brain.[42][50] Sigma receptor activation by methamphetamine promotes methamphetamine-induced
neurotoxicity by facilitating hyperthermia, increasing dopamine synthesis and release, influencing
microglial activation, and modulating apoptotic signaling cascades and the formation of reactive
oxygen species.[42][50]
A 2015 review concluded that the behaviour resulting from the use of methamphetamine is likely
caused in part from the neurotoxic effects of the drug. Excitotoxicity, oxidative stress, metabolic
compromise, UPS dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression and
other processes contributed to this neurotoxicity.[51]

Overdose
A methamphetamine overdose may result in a wide range of symptoms.[9][25] A moderate overdose of
methamphetamine may induce symptoms such as: abnormal heart rhythm, confusion, difficult and/or
painful urination, high or low blood pressure, high body temperature, over-active and/or over-
responsive reflexes, muscle aches, severe agitation, rapid breathing, tremor, urinary hesitancy,
and an inability to pass urine.[9][30] An extremely large overdose may produce symptoms such
as adrenergic storm, methamphetamine psychosis, substantially reduced or no urine
output, cardiogenic shock, bleeding in the brain, circulatory collapse, hyperpyrexia (i.e., dangerously
high body temperature), pulmonary hypertension, kidney failure, rapid muscle breakdown, serotonin
syndrome, and a form of stereotypy ("tweaking").[sources 1] A methamphetamine overdose will likely also
result in mild brain damage due to dopaminergic and serotonergic neurotoxicity.[22][24] Death from
methamphetamine poisoning is typically preceded by convulsions and coma.[25]

Psychosis
Main section: Stimulant psychosis § Substituted amphetamines
Abuse of methamphetamine can result in a stimulant psychosis which may present with a variety of
symptoms (e.g., paranoia, hallucinations, delirium, and delusions).[9][55] A Cochrane
Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine
abuse-induced psychosis states that about 5–15% of users fail to recover completely.[55][56] The same
review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the
symptoms of acute amphetamine psychosis.[55]Amphetamine psychosis may also develop
occasionally as a treatment-emergent side effect.[57]

Emergency treatment
Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments
may initially include administration of activated charcoal and sedation.[9] There is not enough
evidence on hemodialysis or peritoneal dialysis in cases of methamphetamine intoxication to
determine their usefulness.[25] Forced acid diuresis (e.g., with vitamin C) will increase
methamphetamine excretion but is not recommended as it may increase the risk of aggravating
acidosis, or cause seizures or rhabdomyolysis.[9] Hypertension presents a risk for intracranial
hemorrhage (i.e., bleeding in the brain) and, if severe, is typically treated with
intravenous phentolamine or nitroprusside.[9] Blood pressure often drops gradually following sufficient
sedation with a benzodiazepine and providing a calming environment.[9]
Antipsychotics such as haloperidol are useful in treating agitation and psychosis from
methamphetamine overdose.[58][59] Beta blockers with lipophilic properties and CNS penetration such
as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity.[60] The
mixed alpha- and beta-blocker labetalol is especially useful for treatment of concomitant tachycardia
and hypertension induced by methamphetamine.[58] The phenomenon of "unopposed alpha
stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine
toxicity.[58]

Addiction

showAddiction and dependence glossary[61][62][63][64]

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,[65][66] 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.[65][67][68] Phosphorylated CREB increases levels of ΔFosB, which in turn
represses the c-Fos gene with the help of corepressors;[65][69][70] c-Fos repression acts as a molecular switch that
enables the accumulation of ΔFosB in the neuron.[71] 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.[69][70] 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.[69][70]

Current models of addiction from chronic drug use involve alterations in gene expression in certain
parts of the brain, particularly the nucleus accumbens.[72][73] The most important transcription
factors[note 4] that produce these alterations are ΔFosB, cAMP response element binding protein
(CREB), and nuclear factor kappa B (NFκB).[73] ΔFosB plays a crucial role in the development of drug
addictions, since its overexpression in D1-type medium spiny neurons in the nucleus accumbens
is necessary and sufficient[note 5] for most of the behavioral and neural adaptations that arise from
addiction.[62][73][75] Once ΔFosB is sufficiently overexpressed, it induces an addictive state that
becomes increasingly more severe with further increases in ΔFosB expression.[62][75] It has been
implicated in addictions
to alcohol, cannabinoids, cocaine, methylphenidate, nicotine, opioids, phencyclidine, propofol,
and substituted amphetamines, among others.[73][75][76][77][78]
ΔJunD, a transcription factor, and G9a, a histone methyltransferase enzyme, both directly oppose
the induction of ΔFosB in the nucleus accumbens (i.e., they oppose increases in its
expression).[62][73][79] Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral
vectors can completely block many of the neural and behavioral alterations seen in chronic drug
abuse (i.e., the alterations mediated by ΔFosB).[73] ΔFosB also plays an important role in regulating
behavioral responses to natural rewards, such as palatable food, sex, and exercise.[73][76][80] Since
both natural rewards and addictive drugs induce expression of ΔFosB (i.e., they cause the brain to
produce more of it), chronic acquisition of these rewards can result in a similar pathological state of
addiction.[73][76] ΔFosB is the most significant factor involved in both amphetamine addiction and
amphetamine-induced sex addictions, which are compulsive sexual behaviors that result from
excessive sexual activity and amphetamine use.[note 6][76][81] These sex addictions (i.e., drug-induced
compulsive sexual behaviors) are associated with a dopamine dysregulation syndrome which occurs
in some patients taking dopaminergic drugs, such as amphetamine or methamphetamine.[76][80][81]
Epigenetic factors in methamphetamine addiction
Methamphetamine addiction is persistent for many individuals, with 61% of individuals treated for
addiction relapsing within one year.[82] 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.[83]
The frequent persistence of addiction suggests that long-lasting changes in gene expression may
occur in particular regions of the brain, and may contribute importantly to the addiction phenotype.
Recently a crucial role has been found for epigenetic mechanisms in driving lasting changes in gene
expression in the brain.[84]
A review in 2015[85] summarized a number of studies involving chronic methamphetamine use in
rodents. Epigenetic alterations were observed in the brain "reward" regions, including the ventral
tegmental area, the nucleus accumbens, the dorsal striatum, the hippocampus, and the prefrontal
cortex. Chronic methamphetamine use caused gene-specific histone acetylations,
deacetylations and methylations. Gene-specific DNA methylations in particular regions of the brain
were also observed. The various epigenetic alterations caused downregulations or upregulations of
specific genes important in addiction. For instance, chronic methamphetamine use
caused methylation of the lysine in position 4 of histone 3 located at the promoters of the c-fos and
the C-C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens
(NAc).[85] c-fos is well known to be important in addiction.[86] The ccr2 gene is also important in
addiction, since mutational inactivation of this gene impairs addiction.[85]
In methamphetamine addicted rats, epigenetic regulation through reduced acetylation of histones, in
brain striatal neurons, caused reduced transcription of glutamate receptors.[87]Glutamate receptors
play an important role in regulating the reinforcing effects of drugs of abuse.[88]
Treatment and management
Further information: Addiction § Research
Cognitive behavioral therapy is currently the most effective clinical treatment for psychostimulant
addictions in general.[89] As of May 2014, there is no effective pharmacotherapy for
methamphetamine addiction.[90][91][92] Methamphetamine addiction is largely mediated through
increased activation of dopamine receptors and co-localized NMDA receptors[note 7] in the nucleus
accumbens.[67][68] Magnesium ions inhibit NMDA receptors by blocking the receptor calcium
channel.[93][94]

Dependence and withdrawal

Tolerance is expected to develop with regular methamphetamine use and, when used recreationally,
this tolerance develops rapidly.[95][96] In dependent users, withdrawal symptoms are positively
correlated with the level of drug tolerance.[97] Depression from methamphetamine withdrawal lasts
longer and is more severe than that of cocaine withdrawal.[98]
According to the current Cochrane review on drug dependence and withdrawal in recreational users
of methamphetamine, "when chronic heavy users abruptly discontinue [methamphetamine] use,
many report a time-limited withdrawal syndrome that occurs within 24 hours of their last
dose".[97] 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.[97] Methamphetamine withdrawal symptoms can include anxiety, drug craving, dysphoric
 mood, fatigue, increased appetite, increased movement or decreased movement, lack of
motivation, sleeplessness or sleepiness, and vivid or lucid dreams.[97]
Methamphetamine that is present in a mother's bloodstream can pass through the placenta to
a fetus and be secreted into breast milk.[98] Infants born to methamphetamine-abusing mothers may
experience a neonatal withdrawal syndrome, with symptoms involving of abnormal sleep patterns,
poor feeding, tremors, and hypertonia.[98] This withdrawal syndrome is relatively mild and only
requires medical intervention in approximately 4% of cases.[98]

Summary of addiction-related plasticity

Type of reinforcer
lasticity
lasticity
High fat or sugar Sexual Physical exercise Env
Opiates Psychostimulants
food intercourse (aerobic) en

sion in
↑ ↑ ↑ ↑ ↑
1-type MSNs

Behavioral plasticity

ntake Yes Yes Yes

lant
Yes Not applicable Yes Yes Attenuated A
ation

lant
↑ ↑ ↓ ↓
ation

lant
↑ ↑ ↓ ↑ ↓
preference

eeking behavior ↑ ↑ ↓

Neurochemical plasticity
 rylation
↓ ↓ ↓ ↓
cumbens

ne response
No Yes No Yes
cumbens

↑DRD1, ↓DRD2, ↑DRD1, ↓DRD2,

mine signaling ↓DRD2, ↑DRD3 ↑DRD2
↑DRD3 ↑DRD3

No change or ↑μ-opioid receptors ↑μ-opioid

id signaling ↑μ-opioid receptors No change N
↑μ-opioid receptors ↑κ-opioid receptors receptors

↑dynorphin
ioid peptides No ↑dynorphin ↓enkephalin ↑dynorphin ↑
change: enkephalin

Mesocorticolimbic synaptic plasticity

n the nucleus
↓ ↑ ↑
ns

ensity in
↓ ↑ ↑
umbens

Interactions
Methamphetamine is metabolized by the liver enzyme CYP2D6, so CYP2D6 inhibitors will prolong
the elimination half-life of methamphetamine.[99] Methamphetamine also interacts with monoamine
oxidase inhibitors (MAOIs), since both MAOIs and methamphetamine increase plasma
catecholamines; therefore, concurrent use of both is dangerous.[25]Methamphetamine may decrease
the effects of sedatives and depressants and increase the effects of antidepressants and
other stimulants as well.[25] Methamphetamine may counteract the effects
of antihypertensives and antipsychotics due to its effects on the cardiovascular system and cognition
respectively.[25] The pH of gastrointestinal content and urine affects the absorption and excretion of
methamphetamine.[25] Specifically, acidic substances will reduce the absorption of methamphetamine
and increase urinary excretion, while alkaline substances do the opposite.[25] Due to the effect pH has
on absorption, proton pump inhibitors, which reduce gastric acid, are known to interact with
methamphetamine.[25]

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

Pharmacodynamics
Methamphetamine has been identified as a potent full agonist of trace amine-associated receptor
1 (TAAR1), a G protein-coupled receptor (GPCR) that regulates
brain catecholamine systems.[100][101] Activation of TAAR1 increases cyclic adenosine
monophosphate (cAMP) production and either completely inhibits or reverses the transport direction
of the dopamine transporter(DAT), norepinephrine transporter (NET), and serotonin
transporter (SERT).[100][102] When methamphetamine binds to TAAR1, it triggers
transporter phosphorylation via protein kinase A (PKA) and protein kinase C (PKC) signaling,
ultimately resulting in the internalization or reverse function of monoamine
transporters.[100][103] Methamphetamine is also known to increase intracellular calcium, an effect which
is associated with DAT phosphorylation through a Ca2+/calmodulin-dependent protein
kinase (CAMK)-dependent signaling pathway, in turn producing dopamine efflux.[104][105][106] TAAR1
also has been shown to reduce the firing rate of neurons through direct activation of G protein-
coupled inwardly-rectifying potassium channels.[107][108][109] TAAR1 activation by methamphetamine
in astrocytes appears to negatively modulate the membrane expression and function of EAAT2, a
type of glutamate transporter.[49]
In addition to the plasma membrane monoamine transporters, methamphetamine inhibits uptake and
induces efflux of neurotransmitters and other substrates at the vesicular monoamine
transporters, VMAT1 and VMAT2.[110] In neurons, methamphetamine induces monoamine
neurotransmitter efflux through VMAT2, resulting in the outflow of monoamines from synaptic
vesicles into the cytosol (intracellular fluid) of the presynaptic neuron.[111] Other transporters that
methamphetamine is known to inhibit are SLC22A3 and SLC22A5.[110] SLC22A3 is an extraneuronal
monoamine transporter that is present in astrocytes, and SLC22A5 is a high-
affinity carnitine transporter.[101][112]
Methamphetamine is also an agonist of the alpha-2 adrenergic receptors and sigma receptors with a
greater affinity for σ1 than σ2, and inhibits monoamine oxidase A (MAO-A) and monoamine oxidase
B (MAO-B).[42][101][50] Sigma receptor activation by methamphetamine facilitates its central nervous
system stimulant effects and promotes neurotoxicity within the brain.[42][50] Methamphetamine is
known to inhibit the CYP2D6 liver enzyme as well.[99] Dextromethamphetamine is a
stronger psychostimulant (approximately ten times on striatal dopamine),
but levomethamphetamine has stronger peripheral effects, a longer half-life, and longer perceived
effects among addicts.[113][114][115] At high doses, both enantiomers of methamphetamine can induce
similar stereotypy and methamphetamine psychosis,[114] but levomethamphetamine has shorter
psychodynamic effects.[115]

Pharmacokinetics
Following oral administration, methamphetamine is well-absorbed into the bloodstream, with peak
plasma methamphetamine concentrations achieved in approximately 3.13–6.3 hours post
ingestion.[116] Methamphetamine is also well absorbed following inhalation and following intranasal
administration.[9] Due to the high lipophilicity of methamphetamine, it can readily move through
the blood–brain barrier faster than other stimulants, where it is more resistant to degradation
by monoamine oxidase.[9][116] The amphetamine metabolite peaks at 10–
24 hours.[9] Methamphetamine is excreted by the kidneys, with the rate of excretion into the urine
heavily influenced by urinary pH.[25][116] When taken orally, 30–54% of the dose is excreted in urine as
methamphetamine and 10–23% as amphetamine.[116] Following IV doses, about 45% is excreted as
methamphetamine and 7% as amphetamine.[116] The half-life of methamphetamine is variable with a
range of 5–30 hours.[9]
CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase 3, butyrate-CoA ligase,
and glycine N-acyltransferase are the enzymes known to metabolize methamphetamine or its
metabolites in humans.[sources 2] The primary metabolites are amphetamine and 4-
hydroxymethamphetamine;[116] other minor metabolites include: 4-hydroxyamphetamine, 4-
hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine,
and phenylacetone, the metabolites of amphetamine.[3][116][117] Among these metabolites, the
active sympathomimetics are
amphetamine, 4-hydroxyamphetamine,[123] 4-hydroxynorephedrine,[124] 4-
hydroxymethamphetamine,[116] and norephedrine.[125]
The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-
hydroxylation, N-oxidation, N-dealkylation, and deamination.[3][116][126] 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.[116] 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.[127][128]

Detection in biological fluids

Methamphetamine and amphetamine are often measured in urine or blood as part of a drug test for
sports, employment, poisoning diagnostics, and forensics.[129][130][131][132] Chiral techniques may be
employed to help distinguish the source the drug to determine whether it was obtained illicitly or
legally via prescription or prodrug.[133] Chiral separation is needed to assess the possible contribution
of levomethamphetamine, which is an active ingredients in some OTC nasal decongestants,[note
3]
toward a positive test result.[133][134][135] Dietary zinc supplements can mask the presence of
methamphetamine and other drugs in urine.[136]

Chemistry

Pure shards of methamphetamine hydrochloride, also known as crystal meth

Methamphetamine is a chiral compound with two enantiomers, dextromethamphetamine and

levomethamphetamine. At room temperature, the free base of methamphetamine is a clear and
colorless liquid with an odor characteristic of geranium leaves.[11] It is soluble in diethyl
ether and ethanol as well as miscible with chloroform.[11] In contrast, the methamphetamine
hydrochloride salt is odorless with a bitter taste.[11] It has a melting point between 170 to 175 °C (338
to 347 °F) and, at room temperature, occurs as white crystals or a white crystalline powder.[11] The
hydrochloride salt is also freely soluble in ethanol and water.[11]

Degradation
Bleach exposure time and concentration are correlated with destruction of
methamphetamine.[137] Methamphetamine in soils has shown to be a persistent
pollutant.[138] Methamphetamine is largely degraded within 30 days in a study of bioreactors under
exposure to light in wastewater.[139]

Synthesis
Further information on illicit amphetamine synthesis: History and culture of substituted
amphetamines § Illegal synthesis
Racemic methamphetamine may be prepared starting from phenylacetone by either
the Leuckart[140] or reductive amination methods.[141] In the Leuckart reaction, one equivalent of
phenylacetone is reacted with two equivalents of N-methylformamide to produce the formyl amide of
methamphetamine plus carbon dioxide and methylamine as side products.[141]In this reaction,
an iminium cation is formed as an intermediate which is reduced by the second equivalent of N-
methylformamide.[141] The intermediate formyl amide is then hydrolyzed under acidic aqueous
conditions to yield methamphetamine as the final product.[141] Alternatively, phenylacetone can be
reacted with methylamine under reducing conditions to yield methamphetamine.[141]
Methamphetamine synthesis
Method of methamphetamine synthesis of methamphetamine via reductive amination

Methods of methamphetamine synthesis via the Leuckart reaction

History, society, and culture

Main article: History and culture of substituted amphetamines

Pervitin, a methamphetamine brand used by German soldiers during World War II, was dispensed in these
tablet containers.
U.S. drug overdose related fatalities in 2017 were more than 72,000, including 10,721 of those related to
methamphetamine overdose.[142][143]

Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by

Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine.[144][145] Shortly after,
methamphetamine was synthesized from ephedrine in 1893 by Japanese chemistNagai
Nagayoshi.[146] Three decades later, in 1919, methamphetamine hydrochloride was synthesized by
pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.[147]
During World War II, methamphetamine was sold in tablet form under the brand name Pervitin (not
to be confused with Perviton, which is a synonym for Phenatine), produced by the Berlin-
based Temmler pharmaceutical company. It was used extensively by all branches of the
combined Wehrmacht armed forces of the Third Reich, and was popular with Luftwaffe pilots in
particular, for its performance-enhancing stimulant effects and to induce
extended wakefulness.[148][149] Pervitin became colloquially known among the German troops as
"Stuka-Tablets" (Stuka-Tabletten) and "Herman-Göring-Pills" (Hermann-Göring-Pillen). Side effects
were so serious that the army sharply cut back its usage in 1940.[150] Historian Lukasz Kamienski
says "A soldier going to battle on Pervitin usually found himself unable to perform effectively for the
next day or two. Suffering from a drug hangover and looking more like a zombie than a great warrior,
he had to recover from the side effects." Some soldiers turned very violent, committing war crimes
against civilians; others attacked their own officers.[150]
Obetrol, patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of obesity,
was one of the first brands of pharmaceutical methamphetamine products.[151] Due to the
psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in
America in the 1950s and 1960s.[151] Eventually, as the addictive properties of the drug became
known, governments began to strictly regulate the production and distribution of
methamphetamine.[145] For example, during the early 1970s in the United States, methamphetamine
became a schedule II controlled substance under the Controlled Substances Act.[152] Currently,
methamphetamine is sold under the trade name Desoxyn, trademarked by the Danish
pharmaceutical company Lundbeck.[153] As of January 2013, the Desoxyn trademark had been sold
to Italian pharmaceutical company Recordati.[154]