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Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational or performance-enhancing drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder (ADHD). It has also been researched as a potential treatment for traumatic brain injury. Methamphetamine was discovered in 1893 and exists as two : levo-methamphetamine and dextro-methamphetamine. Methamphetamine properly refers to a specific chemical substance, the racemic mixture free base, which is an equal mixture of levomethamphetamine and dextromethamphetamine in their pure amine forms, but the hydrochloride salt, commonly called crystal meth, is widely used. Methamphetamine is rarely prescribed over concerns involving its potential for recreational use as an aphrodisiac and euphoriant, among other concerns, as well as the availability of safer substitute good with comparable treatment efficacy such as Adderall and Vyvanse. While pharmaceutical formulations of methamphetamine in the United States are labeled as methamphetamine hydrochloride, they contain dextromethamphetamine as the active ingredient. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.
Both racemic methamphetamine and dextromethamphetamine are illicitly trafficked and sold owing to their potential for recreational use. The highest prevalence of illegal methamphetamine use occurs in parts of Asia and Oceania, and in the United States, where racemic methamphetamine and dextromethamphetamine are classified as 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. Internationally, the production, distribution, sale, and possession of methamphetamine is restricted or banned in many countries, owing to its placement in schedule II of the United Nations Convention on Psychotropic Substances treaty. While dextromethamphetamine is a more potent drug, racemic methamphetamine is illicitly produced more often, owing to the relative ease of synthesis and regulatory limits of chemical precursor availability.
In low to moderate doses, methamphetamine can euphoria, increase alertness, concentration and energy in fatigued individuals, reduce appetite, and promote weight loss. At very high doses, it can induce psychosis, rhabdomyolysis, seizures, and bleeding in the brain. Chronic high-dose use can precipitate unpredictable and rapid , stimulant psychosis (e.g., paranoia, , delirium, and ), and Aggression. Recreationally, methamphetamine's ability to mental energy has been reported to euphoria and aphrodisiac to such an extent that users are able to engage in sexual activity continuously for several days while binging the drug. 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 drug withdrawal symptoms will occur when methamphetamine use ceases). Discontinuing methamphetamine after heavy use may lead to a post-acute-withdrawal syndrome, which can persist for months beyond the typical Drug withdrawal period. At high doses, methamphetamine is neurotoxicity to human midbrain dopaminergic and, to a lesser extent, serotonin neurons. Methamphetamine neurotoxicity causes adverse changes in brain structure and function, such as reductions in grey matter volume in several brain regions, as well as adverse changes in markers of metabolic integrity.
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 .
Although the pharmaceutical name "methamphetamine hydrochloride" may suggest a racemic mixture, Desoxyn contains Enantiopure drug dextromethamphetamine, which is a more potent stimulant than both levomethamphetamine and racemic methamphetamine. This naming convention deviates from the standard practice observed with other stimulants, such as Adderall and dextroamphetamine, where the dextrorotary enantiomer is explicitly identified as an active ingredient in both Generic drug and brand-name pharmaceuticals.
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. Methamphetamine hydrochloride dispensed in the United States is required to include a boxed warning regarding its potential for recreational misuse and addiction liability.
Desoxyn and Desoxyn Gradumet are both pharmaceutical forms of the drug. The latter is no longer produced and is an extended-release form of the drug, flattening the curve of the effect of the drug while extending it.
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. Participants in this subculture, which consists almost entirely of homosexual male methamphetamine users, will typically meet up through internet dating sites and have sex. Because of its strong stimulant and aphrodisiac effects and inhibitory effect on ejaculation, with repeated use, these sexual encounters will sometimes occur continuously for several days on end. The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia (excessive daytime sleepiness). The party and play subculture is prevalent in major US cities such as San Francisco and New York City. (2025). 9780071605939, McGraw-Hill Medical. ISBN 9780071605939
Besides the sexual transmission of HIV, it may also be transmitted between users who needle sharing. The level of needle sharing among methamphetamine users is similar to that among other drug injection users.
Magnetic resonance imaging studies on human methamphetamine users have also found evidence of neurodegeneration, or adverse neuroplastic changes in brain structure and function. In particular, methamphetamine appears to cause hyperintensity and hypertrophy of white matter, marked shrinkage of Hippocampus, and reduced gray matter in the cingulate cortex, limbic cortex, and paralimbic cortex in recreational methamphetamine users. Moreover, evidence suggests that adverse changes in the level of 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.
Methamphetamine has been shown to activate TAAR1 in human astrocytes and generate cyclic AMP as a result. 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.
Methamphetamine binds to and activates both sigma receptor subtypes, σ1 and σ2, with micromolar affinity. Sigma receptor activation may promote methamphetamine-induced neurotoxicity by facilitating hyperthermia, increasing dopamine synthesis and release, influencing microglial activation, and modulating apoptotic signaling cascades and the formation of reactive oxygen species.
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). Sufficiently overexpressing ΔJunD in the nucleus accumbens with can completely block many of the neural and behavioral alterations seen in chronic drug use (i.e., the alterations mediated by ΔFosB). ΔFosB also plays an important role in regulating behavioral responses to , such as palatable food, sex, and exercise. Since both natural rewards and addictive drugs 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. ΔFosB is the most significant factor involved in both amphetamine addiction and amphetamine-induced , which are compulsive sexual behaviors that result from excessive sexual activity and amphetamine use. 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.
The frequent persistence of addiction suggests that long-lasting changes in gene expression may occur in particular regions of the brain, and may contribute importantly to the addiction phenotype. In 2014, a crucial role was found for epigenetics mechanisms in driving lasting changes in gene expression in the brain.
A review in 2015 summarized a number of studies involving chronic methamphetamine use in rodents. Epigenetic alterations were observed in the brain reward pathways, including areas like ventral tegmental area, nucleus accumbens, and dorsal striatum, the hippocampus, and the prefrontal cortex. Chronic methamphetamine use caused gene-specific histone acetylations, deacetylations and methylations. Gene-specific DNA methylations in particular regions of the brain were also observed. The various epigenetic alterations caused downregulations or upregulations of specific genes important in addiction. For instance, chronic methamphetamine use caused methylation of the lysine in position 4 of histone 3 located at the promoters of the c-fos and the C-C chemokine receptor 2 (ccr2) genes, activating those genes in the nucleus accumbens (NAc). c-fos is well known to be important in addiction. The ccr2 gene is also important in addiction, since mutational inactivation of this gene impairs addiction.
In methamphetamine addicted rats, epigenetic regulation through reduced acetylation of histones, in brain striatal neurons, caused reduced transcription of glutamate receptors. Glutamate receptors play an important role in regulating the reinforcing effects of addictive drugs.
Administration of methamphetamine to rodents causes DNA damage in their brain, particularly in the nucleus accumbens region. During repair of such DNA damages, persistent chromatin alterations may occur such as in the DNA methylation or the acetylation or methylation of histones at the sites of repair. These alterations can be epigenetics in the chromatin that contribute to the persistent epigenetic changes found in methamphetamine addiction.
, there is no effective pharmacotherapy for methamphetamine addiction. A systematic review and meta-analysis from 2019 assessed the efficacy of 17 different pharmacotherapies used in randomized controlled trials (RCTs) for amphetamine and methamphetamine addiction; it found only low-strength evidence that methylphenidate might reduce amphetamine or methamphetamine self-administration. There was low- to moderate-strength evidence of no benefit for most of the other medications used in RCTs, which included antidepressants (bupropion, mirtazapine, sertraline), antipsychotics (aripiprazole), anticonvulsants (topiramate, baclofen, gabapentin), naltrexone, varenicline, citicoline, ondansetron, prometa, riluzole, atomoxetine, dextroamphetamine, and modafinil.
Medication-Assisted Treatment (MAT) combines FDA-approved medications with behavioral therapies to address substance use disorders. This approach aims to reduce cravings and withdrawal symptoms, supporting individuals in their recovery process.
According to the current Cochrane review on drug dependence and 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". 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. Methamphetamine withdrawal symptoms can include anxiety, drug craving, Dysphoria, fatigue, hyperphagia, increased movement or decreased movement, anhedonia, insomnia or hypersomnia, and Lucid dream.
Methamphetamine that is present in a mother's bloodstream can pass through the placenta to a fetus and be secreted into breast milk. Infants born to methamphetamine-abusing mothers may experience a neonatal withdrawal syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and hypertonia. This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.
A prospective cohort study of 330 children showed that at the age of 3, children with methamphetamine exposure showed increased emotional reactivity, as well as more signs of anxiety and depression; and at the age of 5, children showed higher rates of externalizing disorders and attention deficit hyperactivity disorder (ADHD).
Antipsychotics such as haloperidol are useful in treating agitation and psychosis from methamphetamine overdose. with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity. The mixed alpha blocker and beta-blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine. The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.
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| Notes: The smaller the value, the more strongly the drug releases the neurotransmitter. The bioassay were done in rat brain and human potencies may be different. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. Refs: | ||||||
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. 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). When methamphetamine binds to TAAR1, it triggers transporter phosphorylation via protein kinase A (PKA) and protein kinase C (PKC) signaling, ultimately resulting in the endocytosis or reverse function of monoamine transporters. 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. TAAR1 has been shown to reduce the action potential of neurons through direct activation of G protein-coupled inwardly-rectifying potassium channels. TAAR1 activation by methamphetamine in astrocytes appears to negatively modulate the membrane expression and function of EAAT2, a type of glutamate transporter.
In addition to its effect on the plasma membrane monoamine transporters, methamphetamine inhibits synaptic vesicle function by inhibiting VMAT2, which prevents monoamine uptake into the vesicles and promotes their release. This results in the outflow of monoamines from into the cytosol (intracellular fluid) of the presynaptic neuron, and their subsequent release into the synaptic cleft by the phosphorylated transporters. Other transporters that methamphetamine is known to inhibit are SLC22A3 and SLC22A5. SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.
Methamphetamine is also an agonist of the alpha-2 adrenergic receptors and with a greater binding affinity for σ1 than σ2, and inhibits monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). Sigma receptor activation by methamphetamine may facilitate its central nervous system stimulant effects and promote neurotoxicity within the brain. Dextromethamphetamine is a stronger psychostimulant, but levomethamphetamine has stronger peripheral effects, a longer half-life, and longer perceived effects among heavy substance users. At high doses, both enantiomers of methamphetamine can induce similar stereotypy and methamphetamine psychosis, but levomethamphetamine has shorter psychodynamic effects.
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. The primary metabolites are amphetamine and pholedrine; other minor metabolites include: , , , benzoic acid, hippuric acid, norephedrine, and phenylacetone, the metabolites of amphetamine. Among these metabolites, the active sympathomimetics are amphetamine, , , , and norephedrine. Methamphetamine is a CYP2D6 inhibitor.
The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. The known metabolic pathways include:
In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste. It has a melting point between and, at room temperature, occurs as white crystals or a white Crystallinity powder. The hydrochloride salt is also freely soluble in ethanol and water. The crystal structure of either enantiomer is monoclinic with P21 space group; at , it has lattice parameters a = 7.10 Angstrom, b = 7.29 Å, c = 10.81 Å, and β = 97.29°.
From 1938, methamphetamine was marketed on a large scale in Germany as a nonprescription drug under the brand name Pervitin, produced by the Berlin-based Temmler pharmaceutical company. (2025). 9789048124473, Springer. ISBN 9789048124473 It was used by all branches of the combined Wehrmacht of the Third Reich, for its stimulant effects and to induce extended wakefulness. Pervitin became colloquially known among the German troops as "Stuka-Tablets" ( Stuka-Tabletten) and "Herman-Göring-Pills" ( Hermann-Göring-Pillen), as a snide allusion to Göring's widely-known addiction to drugs. However, the side effects, particularly the withdrawal symptoms, were so serious that the army sharply cut back its usage in 1940. 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,
Some soldiers turned violent, committing war crimes against civilians; others attacked their own officers. At the end of the war, it was used as part of a new drug: D-IX.
Obetrol, patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of obesity, was one of the first brands of pharmaceutical methamphetamine products. (2008). 9780814776018, New York University Press. ISBN 9780814776018 Because of the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s. Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine. For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act. As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.
Concerning the accelerating synthetic drug production in the region, the Cantonese Chinese syndicate Sam Gor, also known as , is understood to be the main international crime syndicate responsible for this shift. 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. Sam Gor is alleged to control 40% of the Asia-Pacific methamphetamine market, while also trafficking heroin and ketamine. The organization is active in a variety of countries, including Myanmar, Thailand, New Zealand, Australia, Japan, China, and Taiwan. Sam Gor previously produced meth in Southern China and is now believed to manufacture mainly in the Golden Triangle, specifically Shan State, Myanmar, responsible for much of the massive surge of crystal meth in circa 2019. The group is understood to be headed by Tse Chi Lop, a gangster born in Guangzhou, China who also holds a Canadian passport.
Liu Zhaohua was another individual involved in the production and trafficking of methamphetamine until his arrest in 2005. It was estimated over 18 tonnes of methamphetamine were produced under his watch.
It has been suggested, based on animal research, that calcitriol, the active metabolite of vitamin D, can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of methamphetamine. Protection against methamphetamine-induced neurotoxicity has also been observed following administration of ascorbic acid (vitamin C), cobalamin (vitamin B12), and vitamin E.
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