Methamphetamine
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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 substance, 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 such as Adderall and Vyvanse. Dextroamphetamine 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.[note 3] 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.[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 withdrawal symptoms will occur when methamphetamine use ceases). Withdrawal from methamphetamine after heavy use may lead to a post-acute-withdrawal syndrome, which can persist for months beyond the typical withdrawal period. Methamphetamine is neurotoxic to human midbrain dopaminergic neurons at high doses. Methamphetamine has been shown to have a higher affinity and, as a result, higher toxicity toward serotonergic neurons than amphetamine.[22][23] 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.[23]
In the United States, methamphetamine hydrochloride, under the trade name Desoxyn, has been approved by the FDA for treating ADHD and obesity in both adults and children;[24][25] however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use.[24] Methamphetamine is sometimes prescribed off label for narcolepsy and idiopathic hypersomnia.[26][27] 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.[24] Methamphetamine hydrochloride dispensed in the United States is required to include a boxed warning regarding its potential for recreational misuse and addiction liability.[24]
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.[29] Participants in this subculture, which consists almost entirely of homosexual male methamphetamine users, will typically meet up through internet dating sites and have sex.[29] 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.[29] The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia (excessive daytime sleepiness).[29] The party and play subculture is prevalent in major US cities such as San Francisco and New York City.[29][30]
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.[24] 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.[24] 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.[24] Owing to the potential for stunted growth, the FDA advises monitoring the height and weight of growing children and adolescents during treatment.[24]
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.[24][32] Long-term meth users may have sores on their skin;[33][34][35] these may be caused by scratching due to itchiness[34] or the belief that insects are crawling under their skin,[33] and the damage is compounded by poor diet and hygiene.[35] Numerous deaths related to methamphetamine overdoses have been reported.[36][37]
Methamphetamine users and addicts may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as meth mouth.[38] The condition is generally most severe in users who inject the drug, rather than swallow, smoke, or inhale it.[38] 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)\".[38][39] 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.[25]
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.[40] 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.[40] 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.[24][41] Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.[24][41]
Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle.[42] The level of needle sharing among methamphetamine users is similar to that among other drug injection users.[42]
The psychological effects of methamphetamine can include euphoria, dysphoria, changes in libido, alertness, apprehension and concentration, decreased sense of fatigue, insomnia or wakefulness, self-confidence, sociability, irritability, restlessness, grandiosity and repetitive and obsessive behaviors.[24][32][44] Peculiar to methamphetamine and related stimulants is \"punding\", persistent non-goal-directed repetitive activity.[45] Methamphetamine use also has a high association with anxiety, depression, amphetamine psychosis, suicide, and violent behaviors.[46][47]
Methamphetamine is directly neurotoxic to dopaminergic neurons in both lab animals and humans.[22][23] Excitotoxicity, oxidative stress, metabolic compromise, UPS dysfunction, protein nitration, endoplasmic reticulum stress, p53 expression and other processes contributed to this neurotoxicity.[51][52][53] In line with its dopaminergic neurotoxicity, methamphetamine use is associated with a higher risk of Parkinson's disease.[54] In addition to its dopaminergic neurotoxicity, a review of evidence in humans indicated that high-dose methamphetamine