Methamphetamine[note 1] (contracted from N-methylamphetamine) 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).[23] It has also been researched as a potential treatment for traumatic brain injury.[7] Methamphetamine was discovered in 1893 and exists as two enantiomers: levo-methamphetamine and dextro-methamphetamine.[note 2]Methamphetamine properly refers to a specific chemical substance, the racemicfree 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 drugs with comparable treatment efficacy such as Adderall and Vyvanse.[23] While pharmaceutical formulations of methamphetamine in the United States are labeled as methamphetamine hydrochloride, they contain dextromethamphetamine as the active ingredient.[23][note 3] Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine.[23]
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.[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 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 elevate mood, increase alertness, concentration and energy in fatigued individuals, reduce appetite, and promote weight loss. At very 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 while binging the drug.[28] Methamphetamine is known to possess a high addiction liability (i.e., a high likelihood that long-term or high dose use will lead to compulsive drug use) and high dependence liability (i.e., a high likelihood that withdrawal symptoms will occur when methamphetamine use ceases). Discontinuing methamphetamine after heavy use may lead to a post-acute-withdrawal syndrome, which can persist for months beyond the typical withdrawal period. At high doses, methamphetamine is neurotoxic to human midbraindopaminergicneurons and, to a lesser extent, serotonergic neurons.[29][30] 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.[30]
In the United States, methamphetamine hydrochloride, sold under the brand name Desoxyn, is FDA-approved for the treatment of attention deficit hyperactivity disorder (ADHD);[25][31] however, the FDA notes that the limited therapeutic usefulness of methamphetamine should be weighed against the risks associated with its use.[25] To avoid toxicity and risk of side effects, FDA guidelines recommend an initial dose of methamphetamine at doses 5–10 mg/day for ADHD in adults and children over six years of age, and may be increased at weekly intervals of 5 mg, up to 25 mg/day, until optimum clinical response is found; the usual effective dose is around 20–25 mg/day.[23][7][25] Methamphetamine is sometimes prescribed off-label for obesity, narcolepsy, and idiopathic hypersomnia.[23][32][33] In the United States, methamphetamine's levorotary form is available in some over-the-counter (OTC) nasal decongestant products.[23][note 4]
Although the pharmaceutical name "methamphetamine hydrochloride" may suggest a racemic mixture, Desoxyn contains enantiopure dextromethamphetamine, which is a more potent stimulant than both levomethamphetamine and racemic methamphetamine.[23][note 3] This naming convention deviates from the standard practice observed with other stimulants, such as Adderall and dextroamphetamine, where the dextrorotary enantiomer is explicitly identified as an active ingredient in both generic and brand-name pharmaceuticals.[34][35][36]
Desoxyn and Desoxyn Gradumet are both pharmaceutical forms of the drug. The latter is no longer produced and is a extended-release form of the drug, flattening the curve of the effect of the drug while extending it.[37]
Methamphetamine is often used recreationally for its effects as a potent euphoriant and stimulant as well as aphrodisiac qualities.[38]
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.[38] Participants in this subculture, which consists almost entirely of homosexual male methamphetamine users, will typically meet up through internet dating sites and have sex.[38] 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.[38] The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia (excessive daytime sleepiness).[38] The party and play subculture is prevalent in major US cities such as San Francisco and New York City.[38][39]
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.[40]
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.[48] The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it.[48] 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)".[48][49] 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.[31]
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.[50] 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.[50] 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][51] Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.[25][51]
Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle.[52] The level of needle sharing among methamphetamine users is similar to that among other drug injection users.[52]
Methamphetamine is directly neurotoxic to dopaminergic neurons in both lab animals and humans.[29][30]Excitotoxicity, oxidative stress, metabolic compromise, UPS dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression and other processes contributed to this neurotoxicity.[29][60][4] In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of Parkinson's disease.[61] In addition to its dopaminergic neurotoxicity, a review of evidence in humans indicated that high-dose methamphetamine use can also be neurotoxic to serotonergic neurons.[30] It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine.[62] Withdrawal of methamphetamine in dependent persons may lead to post-acute withdrawal which persists months beyond the typical withdrawal period.[4]
Methamphetamine has been shown to activate TAAR1 in human astrocytes and generate cAMP as a result.[61] 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.[61]
Methamphetamine binds to and activates both sigma receptor subtypes, σ1 and σ2, with micromolar affinity.[59][63] 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.[59][63]
addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences
addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems
dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake)
drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose
drug withdrawal – symptoms that occur upon cessation of repeated drug use
psychological dependence – dependence socially seen as being extremely mild compared to physical dependence (e.g., with enough willpower it could be overcome)
reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them
rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach
sensitization – an amplified response to a stimulus resulting from repeated exposure to it
substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress
tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose
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 glutamateco-release by such psychostimulants,[67][68]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.[67][69][70] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-Fos gene with the help of corepressors;[67][71][72]c-Fosrepression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[73] 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.[71][72] 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.[71][72]
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).[65][75][81] Sufficiently overexpressing ΔJunD in the nucleus accumbens with viral vectors can completely block many of the neural and behavioral alterations seen in chronic drug use (i.e., the alterations mediated by ΔFosB).[75] ΔFosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise.[75][78][82] 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.[75][78] 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 7][78][83] 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.[78][82][83]
Epigenetic factors
Methamphetamine addiction is persistent for many individuals, with 61% of individuals treated for addiction relapsing within one year.[84] 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.[85]
The frequent persistence of addiction suggests that long-lasting changes in gene expression may occur in particular regions of the brain, and may contribute importantly to the addiction phenotype. In 2014, a crucial role was found for epigenetic mechanisms in driving lasting changes in gene expression in the brain.[81]
In methamphetamine addicted rats, epigenetic regulation through reduced acetylation of histones, in brain striatal neurons, caused reduced transcription of glutamate receptors.[88] Glutamate receptors play an important role in regulating the reinforcing effects of addictive drugs.[89]
Administration of methamphetamine to rodents causes DNA damage in their brain, particularly in the nucleus accumbens region.[90][91] During repair of such DNA damages, persistent chromatin alterations may occur such as in the methylation of DNA or the acetylation or methylation of histones at the sites of repair.[92] These alterations can be epigenetic scars in the chromatin that contribute to the persistent epigenetic changes found in methamphetamine addiction.
Tolerance is expected to develop with regular methamphetamine use and, when used recreationally, this tolerance develops rapidly.[97][98] In dependent users, withdrawal symptoms are positively correlated with the level of drug tolerance.[99]Depression from methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.[100]
Methamphetamine that is present in a mother's bloodstream can pass through the placenta to a fetus and be secreted into breast milk.[100] Infants born to methamphetamine-abusing mothers may experience a neonatal withdrawal syndrome, with symptoms involving of abnormal sleep patterns, poor feeding, tremors, and hypertonia.[100] This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.[100]
Unlike other drugs, babies with prenatal exposure to methamphetamine do not show immediate signs of withdrawal. Instead, cognitive and behavioral problems start emerging when the children reach school age.[101]
Use of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g., paranoia, hallucinations, delirium, and delusions).[5][107] A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine use-induced psychosis states that about 5–15% of users fail to recover completely.[107][108] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[107]Amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[109]
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.[110] 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.[111] Unlike fentanyl which causes respiratory depression, methamphetamine is not a respiratory depressant. Some deaths are as a result of intracranial hemorrhage[112] and some deaths are cardiovascular in nature including flash pulmonary edema[113] and ventricular fibrillation.[114][115]
Emergency treatment
Acute methamphetamine intoxication is largely managed by treating the symptoms and treatments may initially include administration of activated charcoal and sedation.[5] 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.[5] Hypertension presents a risk for intracranial hemorrhage (i.e., bleeding in the brain) and, if severe, is typically treated with intravenous phentolamine or nitroprusside.[5] Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment.[5]
Antipsychotics such as haloperidol are useful in treating agitation and psychosis from methamphetamine overdose.[116][117]Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity.[118][failed verification] The mixed alpha- and beta-blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.[116] The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta-blockers for treatment of methamphetamine toxicity.[116]
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).
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.[146] This results in the outflow of monoamines from synaptic vesicles into the cytosol (intracellular fluid) of the presynaptic neuron, and their subsequent release into the synaptic cleft by the phosphorylated transporters.[147] Other transporters that methamphetamine is known to inhibit are SLC22A3 and SLC22A5.[146] SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes, and SLC22A5 is a high-affinity carnitine transporter.[137][148]
The bioavailability of methamphetamine is 67% orally, 79% intranasally, 67 to 90% via inhalation (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.[152] Methamphetamine is also well absorbed following inhalation and following intranasal administration.[5] Because of the high lipophilicity of methamphetamine due to its methyl group, it can readily move through the blood–brain barrier faster than other stimulants, where it is more resistant to degradation by monoamine oxidase.[5][152][153] 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.[25][152] When taken orally, 30–54% of the dose is excreted in urine as methamphetamine and 10–23% as amphetamine.[152] Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine.[152] The elimination half-life of methamphetamine varies with a range of 5–30hours, but it is on average 9 to 12hours in most studies.[5][4] The elimination half-life of methamphetamine does not vary by route of administration, but is subject to substantial interindividual variability.[4]
The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[10][152][163] The known metabolic pathways include:
Metabolic pathways of methamphetamine in humans[sources 2]
The primary metabolites of methamphetamine are amphetamine and 4-hydroxymethamphetamine.[152]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.[164][165]
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.[166][167][168][169] 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.[170] Chiral separation is needed to assess the possible contribution of levomethamphetamine, which is an active ingredients in some OTC nasal decongestants,[note 4] toward a positive test result.[170][171][172] Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.[173]
Chemistry
Shards of pure methamphetamine hydrochloride, also known as crystal meth
In contrast, the methamphetamine hydrochloride salt is odorless with a bitter taste.[13] It has a melting point between 170 and 175 °C (338 and 347 °F) and, at room temperature, occurs as white crystals or a white crystalline powder.[13] The hydrochloride salt is also freely soluble in ethanol and water.[13] The crystal structure of either enantiomer is monoclinic with P21space group; at 90 K (−183.2 °C; −297.7 °F), it has lattice parametersa = 7.10 Å, b = 7.29 Å, c = 10.81 Å, and β = 97.29°.[174]
Degradation
A 2011 study into the destruction of methamphetamine using bleach showed that effectiveness is correlated with exposure time and concentration.[175] A year-long study (also from 2011) showed that methamphetamine in soils is a persistent pollutant.[176] In a 2013 study of bioreactors in wastewater, methamphetamine was found to be largely degraded within 30 days under exposure to light.[177]
Racemic methamphetamine may be prepared starting from phenylacetone by either the Leuckart[178] or reductive amination methods.[179] 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.[179] In this reaction, an iminium cation is formed as an intermediate which is reduced by the second equivalent of N-methylformamide.[179] The intermediate formyl amide is then hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product.[179] Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.[179]
Methamphetamine synthesis
Method of methamphetamine synthesis of methamphetamine via reductive amination
Pervitin, a methamphetamine brand used by German soldiers during World War II, was dispensed in these tablet containers.U.S. drug overdose related fatalities in 2017 were 70,200, including 10,333 of those related to psychostimulants (including methamphetamine).[180][181]
Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine.[182][183] Shortly after, methamphetamine was synthesized from ephedrine in 1893 by Japanese chemistNagai Nagayoshi.[184] Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.[185]
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.[186][187] It was used by all branches of the combined armed forces of the Third Reich, for its stimulant effects and to induce extended wakefulness.[188][189] 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.[190] 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.[190] 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.[191] Because of the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s.[191] Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine.[183] For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act.[192] Currently, methamphetamine is sold under the trade name Desoxyn, trademarked by the Danish pharmaceutical company Lundbeck.[193] As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.[194]
Trafficking
The Golden Triangle (Southeast Asia), specifically Shan State, Myanmar, is the world's leading producer of methamphetamine as production has shifted to Yaba and crystalline methamphetamine, including for export to the United States and across East and Southeast Asia and the Pacific.[195]
Concerning the accelerating synthetic drug production in the region, the Cantonese Chinese syndicate Sam Gor, also known as The Company, is understood to be the main international crime syndicate responsible for this shift.[196] 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.[197] 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.[198] 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.[199] It was estimated over 18 tonnes of methamphetamine were produced under his watch.[199]
The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions.[200][201] In some jurisdictions, it is legally available as a prescription medication. Methamphetamine has been placed in schedule II of the United NationsConvention on Psychotropic Substances treaty, indicating that it has limited medical use.[201]
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.[202] It has also been found that TBI patients testing positive for methamphetamine at the time of emergency department admission have lower rates of mortality.[203]
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.[204] Protection against methamphetamine-induced neurotoxicity has also been observed following administration of ascorbic acid (vitamin C),[205] cobalamin (vitamin B12),[206] and vitamin E.[207]
^Synonyms and alternate spellings include: N-methylamphetamine, desoxyephedrine, Syndrox, Methedrine, and Desoxyn.[14][15][16] Common slang terms for methamphetamine include: meth, speed, crank and shabu (also sabu and shabu-shabu) in Indonesia and the Philippines,[17][18][19][20] and for the hydrochloride crystal, crystal meth, glass, shards, and ice,[21] and, in New Zealand, P.[22]
^Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation. Levomethamphetamine and dextromethamphetamine are also known as L-methamphetamine, (R)-methamphetamine, or levmetamfetamine (International Nonproprietary Name [INN]) and D-methamphetamine, (S)-methamphetamine, or metamfetamine (INN), respectively.[14][24]
^ abThe medication package insert for Desoxyn lists the chemical name (S)-N,α-dimethylbenzeneethanamine hydrochloride, which explicitly identifies the compound as dextromethamphetamine (the S-enantiomer) with no stereochemical ambiguity.[25]
^ abcThe active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.[26][27]
^Transcription factors are proteins that increase or decrease the expression of specific genes.[76]
^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.
^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.
^"Methamphetamine: Toxicity". PubChem Compound. National Center for Biotechnology Information. Archived from the original on 4 January 2015. Retrieved 4 January 2015.
^ abcd"Adderall XR Prescribing Information"(PDF). United States Food and Drug Administration. Shire US Inc. December 2013. pp. 12–13. Archived(PDF) from the original on 30 December 2013. Retrieved 30 December 2013.
^ abCashman 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:10.1016/S0022-3565(24)38081-4. PMID10027866.
^ ab"Methamphetamine". Drug profiles. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). 8 January 2015. Archived from the original on 15 April 2016. Retrieved 27 November 2018. The term metamfetamine (the International Non-Proprietary Name: INN) strictly relates to the specific enantiomer (S)-N,α-dimethylbenzeneethanamine.
^ abcdefghMoszczynska A, Callan SP (September 2017). "Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment". The Journal of Pharmacology and Experimental Therapeutics. 362 (3): 474–488. doi:10.1124/jpet.116.238501. PMC11047030. PMID28630283. METH is a schedule II drug, which can only be prescribed for attention deficit hyperactivity disorder (ADHD), extreme obesity, or narcolepsy (as Desoxyn; Recordati Rare Diseases LLC, Lebanon, NJ), with amphetamine being prescribed more often for these conditions due to amphetamine having lower reinforcing potential than METH (Lile et al., 2013). ... As discussed earlier, the d-enantiomer has stronger CNS effects but is metabolized more quickly than the l-enantiomer, which is longer lasting due to the slower breakdown. ... l-METH, a vasoconstrictor, is the active constituent of the Vicks Inhaler decongestant (Proctor & Gamble, Cincinnati, OH), an over-the-counter product containing about 50 mg of the drug (Smith et al., 2014). Desoxyn, which is d-METH, is rarely medically prescribed due to its strong reinforcing properties. Therapeutic doses of Desoxyn are 20–25 mg daily, taken every 12 hours, with dosing not exceeding 60 mg/day
^"Levomethamphetamine". Pubchem Compound. National Center for Biotechnology Information. Archived from the original on 6 October 2014. Retrieved 27 November 2018.
^ abcdefghKrasnova IN, Cadet JL (May 2009). "Methamphetamine toxicity and messengers of death". Brain Res. Rev. 60 (2): 379–407. doi:10.1016/j.brainresrev.2009.03.002. PMC2731235. PMID19328213. 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).
^ abcdWestfall DP, Westfall TC (2010). "Miscellaneous Sympathomimetic Agonists". In Brunton LL, Chabner BA, Knollmann BC (eds.). Goodman & Gilman's Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill. ISBN978-0-07-162442-8. Archived from the original on 10 November 2013. Retrieved 1 January 2014.
^ abElkins C (27 February 2020). "Meth Sores". DrugRehab.com. Advanced Recovery Systems. Archived from the original on 14 August 2020. Retrieved 15 March 2020.
^National Institute on Drug Abuse (29 January 2021). "Overdose Death Rates". National Institute on Drug Abuse. Archived from the original on 25 January 2018. Retrieved 8 October 2020.
^ abcHussain 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. PMID22782046.
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^ abBeardsley 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:10.1016/B978-0-12-420118-7.00001-9. ISBN978-0-12-420118-7. PMC4103010. PMID24484974. 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
^ abcdeKaushal N, Matsumoto RR (March 2011). "Role of sigma receptors in methamphetamine-induced neurotoxicity". Curr Neuropharmacol. 9 (1): 54–57. doi:10.2174/157015911795016930. PMC3137201. PMID21886562. 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].
^Yuan J, Hatzidimitriou G, Suthar P, Mueller M, McCann U, Ricaurte G (March 2006). "Relationship between temperature, dopaminergic neurotoxicity, and plasma drug concentrations in methamphetamine-treated squirrel monkeys". The Journal of Pharmacology and Experimental Therapeutics. 316 (3): 1210–1218. doi:10.1124/jpet.105.096503. PMID16293712. S2CID11909155.
^ abcdRodvelt KR, Miller DK (September 2010). "Could sigma receptor ligands be a treatment for methamphetamine addiction?". Curr Drug Abuse Rev. 3 (3): 156–162. doi:10.2174/1874473711003030156. PMID21054260.
^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. ISBN9780071481274.
^ abcdNestler EJ (December 2013). "Cellular basis of memory for addiction". Dialogues in Clinical Neuroscience. 15 (4): 431–443. PMC3898681. PMID24459410. 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.
^Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". New England Journal of Medicine. 374 (4): 363–371. doi:10.1056/NEJMra1511480. PMC6135257. PMID26816013. 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.
^ abcRenthal W, Nestler EJ (September 2009). "Chromatin regulation in drug addiction and depression". Dialogues in Clinical Neuroscience. 11 (3): 257–268. doi:10.31887/DCNS.2009.11.3/wrenthal. PMC2834246. PMID19877494. [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
^Broussard JI (January 2012). "Co-transmission of dopamine and glutamate". The Journal of General Physiology. 139 (1): 93–96. doi:10.1085/jgp.201110659. PMC3250102. PMID22200950. 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.
^Kanehisa Laboratories (10 October 2014). "Amphetamine – Homo sapiens (human)". KEGG Pathway. Retrieved 31 October 2014. Most addictive drugs increase extracellular concentrations of dopamine (DA) in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), projection areas of mesocorticolimbic DA neurons and key components of the "brain reward circuit". Amphetamine achieves this elevation in extracellular levels of DA by promoting efflux from synaptic terminals. ... Chronic exposure to amphetamine induces a unique transcription factor delta FosB, which plays an essential role in long-term adaptive changes in the brain.
^ abcRobison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nature Reviews Neuroscience. 12 (11): 623–637. doi:10.1038/nrn3111. PMC3272277. PMID21989194. 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
^ abcNestler EJ (December 2012). "Transcriptional mechanisms of drug addiction". Clinical Psychopharmacology and Neuroscience. 10 (3): 136–143. doi:10.9758/cpn.2012.10.3.136. PMC3569166. PMID23430970. 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
^Nestler EJ (October 2008). "Transcriptional mechanisms of addiction: Role of ΔFosB". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1507): 3245–3255. doi:10.1098/rstb.2008.0067. PMC2607320. PMID18640924. 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
^ abcdefghRobison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci. 12 (11): 623–637. doi:10.1038/nrn3111. PMC3272277. PMID21989194. 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.
^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. ISBN978-0-07-148127-4.
^ abcRuffle JK (November 2014). "Molecular neurobiology of addiction: what's all the (Δ)FosB about?". Am. J. Drug Alcohol Abuse. 40 (6): 428–437. doi:10.3109/00952990.2014.933840. PMID25083822. S2CID19157711. ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure.
^ abcdefghijklmnopqrOlsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology. 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC3139704. PMID21459101. 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).
^ abBlum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, et al. (March 2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". Journal of Psychoactive Drugs. 44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC4040958. PMID22641964. 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.
^ abPitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM (February 2013). "Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator". J. Neurosci. 33 (8): 3434–3442. doi:10.1523/JNEUROSCI.4881-12.2013. PMC3865508. PMID23426671. Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity
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^ abcShoptaw SJ, Kao U, Ling W (2009). Shoptaw SJ, Ali R (eds.). "Treatment for amphetamine psychosis". Cochrane Database Syst. Rev. 2009 (1): CD003026. doi:10.1002/14651858.CD003026.pub3. PMC7004251. PMID19160215. 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.
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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
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