Methamphetamine

This article is about the psychostimulant drug, methamphetamine, in both racemic and dextrorotatory forms. For the CNS inactive OTC nasal decongestant, see levomethamphetamine.

Methamphetamine

Clinical data
Other names	Desoxyephedrine Methamfetamine Pervitin Anadrex Methedrine Methylamphetamine Syndrox Desoxyn
Routes of administration	Medical: Ingestion Recreational: Ingestion, Intravenous, Insufflation, Inhalation, Suppository
ATC code	N06BA03 (WHO)
Legal status
Legal status	AU: S8 (Controlled drug) CA: Schedule I US: Schedule II Class A(NZ) Schedule 5(SA) Injectable:Class A, Oral: A(UK)
Pharmacokinetic data
Bioavailability	62.7% oral; 79% nasal; 90.3% smoked; 99% rectally; 100% IV
Metabolism	Hepatic
Elimination half-life	9–12 hours
Excretion	Renal
Identifiers
IUPAC name N-methyl-1-phenylpropan-2-amine
CAS Number	537-46-2 Y
PubChem CID	1206
DrugBank	DB01577 Y
ChemSpider	1169 N
UNII	44RAL3456C
KEGG	D08187 Y
ChEBI	CHEBI:6809 Y
ChEMBL	ChEMBL1201201 Y
CompTox Dashboard (EPA)	DTXSID8037128
ECHA InfoCard	100.007.882
Chemical and physical data
Formula	C10H15N
Molar mass	149.233 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES N(C(Cc1ccccc1)C)C
InChI InChI=1S/C10H15N/c1-9(11-2)8-10-6-4-3-5-7-10/h3-7,9,11H,8H2,1-2H3 N Key:MYWUZJCMWCOHBA-UHFFFAOYSA-N N
NY (what is this?)  (verify)

Methamphetamine (USAN) (/ˌmɛθæmˈfɛtəmiːn/), also known as methamfetamine (INN), meth, N-methylamphetamine, methylamphetamine, and desoxyephedrine, is a psychostimulant of the phenethylamine and amphetamine class of psychoactive drugs.

Methamphetamine increases alertness, concentration, energy, and in high doses, can induce euphoria, enhance self-esteem and increase libido. Methamphetamine has high potential for abuse and addiction, activating the psychological reward system by triggering a cascading release of dopamine in the brain. Methamphetamine is FDA approved for the treatment of ADHD and exogenous obesity. It is dispensed in the USA under the trademark name Desoxyn and manufactured by Ovation Pharmaceuticals which was purchased in 2009 by Danish pharmaceutical Lundbeck.

Withdrawal

Withdrawal symptoms of methamphetamine primarily consist of fatigue, depression and an increased appetite. Symptoms may last for days with occasional use and weeks or months with chronic use, with severity dependent on the length of time and the amount of methamphetamine used. Withdrawal symptoms may also include anxiety, irritability, headaches, agitation, akathisia, hypersomnia (excessive sleeping), vivid or lucid dreams, deep REM sleep and suicidal ideation.

Long-term

Methamphetamine use has a high association with depression and suicide as well as serious heart disease, amphetamine psychosis, anxiety and violent behaviors. Methamphetamine also has a very high addiction risk. Methamphetamine is not directly neurotoxic but its use is associated with an increased risk of Parkinson's disease due to the fact that uncontrolled dopamine release is neurotoxic. Long-term dopamine upregulation occurring as a result of Methamphetamine abuse can cause neurotoxicity which is believed to be responsible for causing persisting cognitive deficits, such as memory, impaired attention and executive function. Over 20 percent of people addicted to methamphetamine develop a long-lasting psychosis resembling schizophrenia after stopping methamphetamine which persists for longer than 6 months and is often treatment resistant. Methamphetamine use is frequently comorbid with other mental health issues, especially clinical depression, likely due to its dopaminergic qualities. (Dopamine imbalances are often implicated in psychological health problems.)

Tolerance

As with other amphetamines, tolerance to methamphetamine is not completely understood but known to be sufficiently complex that it cannot be explained by any single mechanism. The extent of tolerance and the rate at which it develops vary widely between individuals, and, even within one person, it is highly dependent on dosage, duration of use, and frequency of administration. Tolerance to the awakening effect of amphetamines does not readily develop, making them suitable for the treatment of narcolepsy.

Short-term tolerance can be caused by depleted levels of neurotransmitters within the synaptic vesicles available for release into the synaptic cleft following subsequent reuse (tachyphylaxis). Short-term tolerance typically lasts until neurotransmitter levels are fully replenished; because of the toxic effects on dopaminergic neurons, this can be greater than 2–3 days. Prolonged overstimulation of dopamine receptors caused by methamphetamine may eventually cause the receptors to downregulate in order to compensate for increased levels of dopamine within the synaptic cleft. To compensate, larger quantities of the drug are needed in order to achieve the same level of effects.

Reverse tolerance or sensitization can also occur. The effect is well established, but the mechanism is not well understood.

Adverse effects

Addiction

Methamphetamine is highly addictive. While the withdrawal itself may not be dangerous, withdrawal symptoms are common with heavy use and relapse is common.

Methamphetamine-induced hyperstimulation of pleasure pathways can lead to anhedonia months after use has been discontinued. Investigation of treatments targeting dopamine signalling such as bupropion, or psychological treatments that raise hedonic tone, such as behavioral activation therapy, have been suggested. It is possible that daily administration of the amino acids L-tyrosine and L-5HTP/tryptophan can aid in the recovery process by making it easier for the body to reverse the depletion of dopamine, norepinephrine, and serotonin. Although studies involving the use of these amino acids have shown some success, this method of recovery has not been shown to be consistently effective.

It is shown that taking ascorbic acid prior to using methamphetamine may help reduce acute toxicity to the brain, as rats given the human equivalent of 5–10 grams of ascorbic acid 30 minutes prior to methamphetamine dosage had toxicity mediated, yet this will likely be of little avail in solving the other serious behavioral problems associated with methamphetamine use and addiction that many users experience. Large doses of ascorbic acid also lower urinary pH, reducing methamphetamine's elimination half-life and thus decreasing the duration of its actions.

To combat addiction, doctors are beginning to use other forms of stimulants such as dextroamphetamine, the dextrorotatory (right-handed) isomer of the amphetamine molecule, to break the addiction cycle in a method similar to the use of methadone in the treatment of heroin addicts. There are no publicly available drugs comparable to naloxone, which blocks opiate receptors and is therefore used in treating opiate dependence, for use with methamphetamine problems. However, experiments with some monoamine reuptake inhibitors such as indatraline have been successful in blocking the action of methamphetamine. There are studies indicating that fluoxetine, bupropion and imipramine may reduce craving and improve adherence to treatment. Research has also suggested that modafinil can help addicts quit methamphetamine use.

Methamphetamine addiction is one of the most difficult forms of addictions to treat. Bupropion, aripiprazole, and baclofen have been employed to treat post-withdrawal cravings, although the success rate is low. Modafinil is somewhat more successful, but this is a Class IV scheduled drug. Ibogaine has been used with success in Europe, where it is a Class I drug and available only for scientific research. Mirtazapine has been reported useful in some small-population studies.

As the phenethylamine phentermine is a constitutional isomer of methamphetamine, it has been suggested that it may be effective in treating methamphetamine addiction. Phentermine is a central nervous system stimulant that acts on dopamine and norepinephrine. When comparing (+)-amphetamine, (+/-)-ephedrine, and phentermine, one key difference among the three drugs is their selectivity for norepinephrine (NE) release vs. dopamine (DA) release. The NE/DA selectivity ratios for these drugs as determined in vitro [(EC(50) NE(-1))/(EC(50) DA(-1))] are (+/-)-ephedrine (18.6) > phentermine (6.7) > (+)-amphetamine (3.5).

Abrupt interruption of chronic methamphetamine use results in the withdrawal syndrome in almost 90% of the cases.

The mental depression associated with methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.

Meth mouth

Main article: Meth mouth

Methamphetamine users and addicts may lose their teeth abnormally quickly, a condition informally known as meth mouth. 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)". Some reports have also speculated that the caustic nature of the drug is a contributing factor. Similar, though far less severe, symptoms have been reported in clinical use of regular amphetamine, where effects are not exacerbated by extended periods of poor oral hygiene.

Public health issues

Waste left behind from a methamphetamine lab

Short-term exposure to high concentrations of chemical vapors that may exist in methamphetamine laboratories can cause severe health problems or even result in death. Exposure to these substances can occur from volatile air emissions, spills, fires, and explosions. Methamphetamine labs are often discovered when fire fighters respond to a blaze. Methamphetamine cooks, their families, and first responders are at highest risk of acute health effects from chemical exposure, including lung damage and chemical burns to the body. Following a seizure of a methamphetamine lab, there is often a low exposure risk to chemical residues, however this contamination should be sanitized. Chemical residues and lab wastes that are left behind at a former methamphetamine lab can result in severe health problems for people who use the property, therefore local health departments should thoroughly assess the property for hazards prior to allowing it to be reinhabited, especially by children. Those seeking home ownership in heavy meth use areas should be especially careful while house hunting and be sure to have properties inspected before purchasing.

Pregnancy and breastfeeding

Methamphetamine present in a mother's bloodstream passes through the placenta to a fetus, and is also secreted into breast milk. Infants born to methamphetamine-abusing mothers were found to have a significantly smaller gestational age-adjusted head circumference and birth weight measurements. Methamphetamine exposure was also associated with neonatal withdrawal symptoms of agitation, vomiting and tachypnea. This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.

Risk of sexually transmitted disease

See also: Sexually transmitted disease, Sex and drugs, and Party and play

Men who use methamphetamine, cocaine, MDMA, and ketamine, are twice as likely to have unprotected sex than those who do not use such drugs, according to British research. American psychologist Perry N. Halkitis performed an analysis using data collected from community-based participants among gay and bisexual men to examine the associations between their methamphetamine use and sexual risk taking behaviors. Methamphetamine use was found to be related to higher frequencies of unprotected sexual intercourse in both HIV-positive and unknown casual partners in the study population. The association between methamphetamine use and unprotected acts were also more pronounced in HIV-positive participants. These findings suggested that methamphetamine use and engagement in unprotected anal intercourse are co-occurring risk behaviors that potentially heighten the risk of HIV transmission among gay and bisexual men. Methamphetamine allows users of both sexes to engage in prolonged sexual activity, which may cause genital sores and abrasions. Methamphetamine can also cause sores and abrasions in the mouth via bruxism (teeth clenching and grinding), which can turn typically low-risk sex acts, such as oral sex, into high-risk sexual activity. As with the injection of any drug, if a group of users share a common needle, blood-borne diseases, such as HIV or hepatitis, can be transmitted. The level of needle sharing among methamphetamine users is similar to that among other drug injection users.

Pharmacokinetics

Illustration depicting normal operation of the dopaminergic terminal to the left, and the dopaminergic terminal in presence of amphetamines to the right. Note the reverse action of the dopamine transporter (DAT), the vesicular monoamine transporter (VMAT) and the decrease of the standard vesicular neurotransmitter efflux. Amphetamine allows dopamine to transit in both directions (blue & red arrows) from the terminal, unlike dopamine reuptake inhibitors (such as cocaine) which block dopamine reentry at both the terminal and at the reuptake pump, whereas dopamine releasing agents allow reentries and exits from both.

Following oral administration, methamphetamine is readily absorbed into the bloodstream, with peak plasma concentrations achieved in approximately 3.13 to 6.3 hours post ingestion. The amphetamine metabolite peaks at 10 to 24 hours. Methamphetamine is also well absorbed following inhalation and following intranasal administration. It is distributed to most parts of the body. Methamphetamine is known to produce central effects similar to the other stimulants, but at smaller doses, with fewer peripheral effects. Methamphetamine's high lipophilicity also allows it to cross the blood brain barrier faster than other stimulants, where it is more stable against degradation by monoamine oxidase (MAO).

Methamphetamine is metabolized in the liver with the main metabolites being amphetamine (active) and 4-hydroxymethamphetamine (pholedrine); other minor metabolites include 4-hydroxyamphetamine, norephedrine, and 4-hydroxynorephedrine. Other drugs metabolized to amphetamine and methamphetamine include benzphetamine, furfenorex, and famprofazone. Selegiline (marketed as Deprenyl, EMSAM, and others) is metabolized into the less active L-isomer of amphetamine and the inactive L-isomer of methamphetamine. Although only the D-Isomer of selegiline will metabolize into active metabolites, both isomers may cause a positive result for methamphetamine and amphetamine on a drug test, in certain cases.

It is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH. Between 30-54% of an oral dose is excreted in urine as unchanged methamphetamine and 10-23% as unchanged amphetamine. Following an intravenous dose, 45% is excreted as unchanged parent drug and 7% amphetamine. The half-life of methamphetamine is variable with a mean value of between 9 and 12 hours.

Detection in biological fluids

Methamphetamine and amphetamine are often measured in urine, sweat or saliva as part of a drug-abuse testing program, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or in whole blood to assist in a forensic investigation of a traffic or other criminal violation or a case of sudden death. Chiral techniques may be employed to help distinguish the source of the drug, whether obtained legally (via prescription) or illicitly, or possibly as a result of formation from a prodrug such as famprofazone or selegiline. Chiral separation is needed to assess the possible contribution of l-methamphetamine (Vicks Inhaler) toward a positive test result. In 2011, researchers at John Jay College of Criminal Justice reported that dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine. Similar claims have been made in web forums on that topic.

Pharmacology

A member of the family of phenethylamines, methamphetamine is chiral, with two isomers, levorotatory and dextrorotatory. The levorotatory form, called levomethamphetamine, is an over-the-counter drug used in inhalers for nasal decongestion. Levomethamphetamine (a levoamphetamine derivative) does not possess any significant central nervous system activity or addictive properties. This article deals only with the dextrorotatory form, called dextromethamphetamine, and the racemic form.

Methamphetamine is a potent central nervous system stimulant that affects neurochemical mechanisms responsible for regulating heart rate, body temperature, blood pressure, appetite, attention, mood and emotional responses associated with alertness or alarming conditions. The acute physical effects of the drug closely resemble the physiological and psychological effects of an epinephrine-provoked fight-or-flight response, including increased heart rate and blood pressure, vasoconstriction (constriction of the arterial walls), bronchodilation, and hyperglycemia (increased blood sugar). Users experience an increase in focus, increased mental alertness, and the elimination of fatigue, as well as a decrease in appetite. It is known to produce central effects similar to the other stimulants, but at smaller doses, with fewer peripheral effects. Methamphetamine's fat solubility also allows it to enter the brain faster than other stimulants, where it is more stable against degradation by monoamine oxidase (MAO).

File:Methamphetamine2.png

Ball-and-stick model of the methamphetamine molecule

The methyl group is responsible for the potentiation of effects as compared to the related compound amphetamine, rendering the substance more lipid-soluble, enhancing transport across the blood-brain barrier, and more stable against enzymatic degradation by monoamine oxidase (MAO). Methamphetamine causes the norepinephrine, dopamine, and serotonin (5HT) transporters to reverse their direction of flow. This inversion leads to a release of these transmitters from the vesicles to the cytoplasm and from the cytoplasm to the synapse (releasing monoamines in rats with ratios of about NE:DA = 1:2, NE:5HT = 1:60), causing increased stimulation of post-synaptic receptors. Methamphetamine also indirectly prevents the reuptake of these neurotransmitters, causing them to remain in the synaptic cleft for a prolonged period (inhibiting monoamine reuptake in rats with ratios of about: NE:DA = 1:2.35, NE:5HT = 1:44.5). Methamphetamine also interacts with TAAR1 to trigger phosphorylation of PKA and PKC, ultimately resulting in the internalization of dopamine transporters. The presynaptic cell is less able to effectively remove dopamine from the synapse. The binding of methamphetamine to TAAR1 also activates adenylyl cyclase, which allows for increased intracellular cAMP. Taken together, the binding of methamphetamine to TAAR1 results in a massive efflux of neurogenic monoamines with a sustained synaptic presence.

Methamphetamine is a potent neurotoxin, shown to cause dopaminergic degeneration. High doses of methamphetamine produce losses in several markers of brain dopamine and serotonin neurons. Dopamine and serotonin concentrations, dopamine and 5HT uptake sites, and tyrosine and tryptophan hydroxylase activities are reduced after the administration of methamphetamine. It has been proposed that dopamine plays a role in methamphetamine-induced neurotoxicity, because experiments that reduce dopamine production or block the release of dopamine decrease the toxic effects of methamphetamine administration. When dopamine breaks down, it produces reactive oxygen species such as hydrogen peroxide. It is likely that the approximate twelvefold increase in dopamine levels and subsequent oxidative stress that occurs after taking methamphetamine mediates its neurotoxicity. The lab of David Sulzer and colleagues at Columbia University developed a technique known as "intracellular patch electrochemistry" to measure concentrations of dopamine in the cytosol, and found massive increases following methamphetamine, leading to the "cytosolic dopamine hypothesis" of neurotoxicity, in which dopamine oxidation, particularly close to synaptic vesicles, produce oxidative stress that in turn leads to exacerbation of autophagy that can destroy axons and dendrites.

Recent research published in the Journal of Pharmacology And Experimental Therapeutics (2007) indicates that methamphetamine binds to and activates a G protein-coupled receptor called TAAR1. TAARs are a newly discovered receptor family whose members are activated by a number of amphetamine-like molecules called trace amines, thyronamines, and certain volatile odorants.

It has been demonstrated that a high ambient temperature increases the neurotoxic effects of methamphetamine.

Natural occurrence

Methamphetamine has been reported to occur naturally in Acacia berlandieri, and possibly Acacia rigidula, trees that grow in West Texas. Methamphetamine and amphetamine were long thought to be strictly human-synthesized, but Acacia trees contain these and numerous other psychoactive compounds (e.g., mescaline, nicotine, dimethyltryptamine), and the related compound β-phenethylamine is known to occur from numerous Acacia species. The findings, however, have never been confirmed or repeated, leading some researchers to believe the results were the result of cross-contamination.

Routes of administration

Glass pipe used for smoking methamphetamine

Studies have shown that the subjective pleasure of drug use (the reinforcing component of addiction) is proportional to the rate at which the blood level of the drug increases. These findings suggest the route of administration used affects the potential risk for psychological addiction independently of other risk factors, such as dosage and frequency of use. Intravenous injection is the fastest route of drug administration, causing blood concentrations to rise the most quickly, followed by smoking, suppository (anal or vaginal insertion), insufflation (snorting), and ingestion (swallowing). Ingestion does not produce a rush, an acute transcendent state of euphoria as forerunner to the high experienced with the use of methamphetamine, which is most pronounced with the intravenous route of administration. Whilst the onset of the rush induced by injection can occur in as little as a few seconds, the oral route of administration requires approximately half an hour before the high sets in.

Injection

Injection carries relatively greater risks than other methods of administration. The hydrochloride salt of methamphetamine is soluble in water. Intravenous users may use any dose range, from less than 100 milligrams to over one gram, using a hypodermic needle, although it should be noted that typically street methamphetamine is "cut" with a water-soluble cutting material, which constitutes a significant portion of a given street methamphetamine dose. Intravenous users risk developing pulmonary embolism (PE), a blockage of the main artery of the lung or one of its branches, and commonly develop skin rashes (also known as "speed bumps") or infections at the site of injection. As with the injection of any drug, if a group of users share a common needle without sterilization procedures, blood-borne diseases, such as HIV or hepatitis, can be transmitted.

Smoking

Smoking amphetamines refers to vaporizing it to inhale the resulting fumes, not burning it to inhale the resulting smoke. It is commonly smoked in glass pipes made from glassblown Pyrex tubes and light bulbs. It can also be smoked off aluminium foil, which is heated underneath by a flame. This method is also known as "chasing the white dragon" (whereas smoking heroin is known as "chasing the dragon"). There is little evidence that methamphetamine inhalation results in greater toxicity than any other route of administration. Lung damage has been reported with long-term use, but manifests in forms independent of route (pulmonary hypertension (PH)), or limited to injection users (pulmonary embolism (PE)).

Insufflation

Another popular route of administration to intake methamphetamine is insufflation (snorting). This method allows methamphetamine to be absorbed through the soft tissue of the mucous membrane in the sinus cavity, and then directly into the bloodstream, bypassing first-pass metabolism.

Suppository

Suppository (anal or vaginal insertion) is a less popular method of administration used in the community with comparatively little research into its effects. Information on its use is largely anecdotal with reports of increased sexual pleasure and the effects of the drug lasting longer, though as methamphetamine is centrally active in the brain, these effects are likely experienced through the higher bioavailability of the drug in the bloodstream (second to injection) and the faster onset of action (than insufflation). Nicknames for the route of administration within some methamphetamine communities include a "butt rocket", a "booty bump", "potato thumping", "turkey basting", "plugging", "boofing", "suitcasing", "hooping", "keistering", "shafting", "bumming", and "shelving" (vaginal).

History

Crystal methamphetamine was first synthesized in 1919 by Akira Ogata

Discovery

Shortly after the first synthesis of amphetamine in 1887, methamphetamine was first synthesized from ephedrine in Japan in 1893 by chemist Nagai Nagayoshi. The term "methamphetamine" was derived from elements of the chemical structure of this new compound: methyl alpha-methylphenylethylamine. In 1919, crystallized methamphetamine was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.

Military use

One of the earliest uses of methamphetamine was during World War II, when it was used by Axis and Allied forces. The company Temmler produced methamphetamine under the trademark Pervitin and so did the German and Finnish militaries. It was also dubbed "Pilot's chocolate" or "Pilot's salt". It was widely distributed across rank and division, from elite forces to tank crews and aircraft personnel, with many millions of tablets being distributed throughout the war. More than 35 million three-milligram doses of Pervitin and the closely related Isophan were manufactured for the German army and air force between April and July 1940. From 1942 until his death in 1945, Adolf Hitler may have been given intravenous injections of methamphetamine by his personal physician Theodor Morell. It is possible that it was used to treat Hitler's speculated Parkinson's disease, or that his Parkinson-like symptoms that developed from 1940 onwards resulted from using methamphetamine. In Japan, methamphetamine was sold under the registered trademark of Philopon (ヒロポン hiropon) by Dainippon Pharmaceuticals (present-day Dainippon Sumitomo Pharma) for civilian and military use. As with the rest of the world at the time, the side effects of methamphetamine were not well studied, and regulation was not seen as necessary. In the 1940s and 1950s the drug was widely administered to Japanese industrial workers to increase their productivity.

Methamphetamine and amphetamine were given to Allied bomber pilots to sustain them by fighting off fatigue and enhancing focus during long flights. The experiment failed because soldiers became agitated, could not channel their aggression and showed impaired judgment. Rather, dextroamphetamine (Dexedrine) became the drug of choice for American bomber pilots, being used on a voluntary basis by roughly half of the United States Air Force pilots during the 1991 Gulf War, a practice which came under some media scrutiny in 2003 after a mistaken attack on Canadian troops.

Medical and legal over-the-counter sales

Following the use of amphetamine (such as Benzedrine, introduced 1932) in the 1930s for asthma, narcolepsy, and symptoms of the common cold, in 1943, Abbott Laboratories requested FDA approval of methamphetamine for treatment of narcolepsy, mild depression, postencephalitic parkinsonism, chronic alcoholism, cerebral arteriosclerosis, and hay fever, which was granted December, 1944.

Sale of the massive postwar surplus of methamphetamine in Europe, North America, and Japan stimulated civilian demand. After World War II, a large Japanese military stockpile of methamphetamine, known by its trademark Philopon, flooded the market. Post-war Japan experienced the first methamphetamine epidemic, which later spread to Guam, the U.S. Marshall Islands and to the U.S. West Coast.

In the 1950s, there was a rise in the legal prescription of methamphetamine to the American public. In the 1954 edition of Pharmacology and Therapeutics, indications for methamphetamine included "narcolepsy, postencephalitic parkinsonism, alcoholism, certain depressive states, and in the treatment of obesity." Methamphetamine constituted half of the amphetamine salts for the original formulation for the diet drug Obetrol which later became Adderall. Methamphetamine was also marketed for sinus inflammation or for non-medicinal purposes as "pep pills" or "bennies". The 1960s saw the start of significant use of clandestinely manufactured methamphetamine, most of which was produced by motorcycle gangs, as well it being prescribed by San Franciscan drug clinics to treat heroin addiction. Beginning in the 1990s, the production of methamphetamine in users' own homes for personal and recreational use became popular and continues to be to this day.

By the 2000s, the only two FDA approved marketing indications remaining for methamphetamine were for attention-deficit hyperactivity disorder (ADHD) and the short-term management of exogenous obesity, although the drug is clinically established as effective in the treatment of narcolepsy.

Trademark Litigation

In 1948, the Philopon trademark came under a well-publicized lawsuit by Philips Corporation. Philips under its Koninklijke division filed suit against Dainippon Pharmaceuticals to cease using Philipon as the commercial name for methamphetamine claiming that they had the exclusive right to use the trademark as a portmanteau of Philips and Nippon, the Japanese name of the country. DSP's attorneys challenged Philips' standing to sue as a foreign (Dutch) corporation. The matter was ultimately settled out of court in 1952, with Dainippon Pharmaceuticals agreeing to pay Philips a 5% royalty on worldwide sales of methamphetamines sold by DSP under the Philopon label. The Japanese Ministry of Health banned production less than a year later.

Recreational use and prohibitive regulations

In 1950 the Japanese Ministry of Health banned stimulant production but drug companies continued to produce stimulants and they wound up on the black market. From 1951 to 1954 a series of acts were passed by the Japanese government to try to stop production and sale of stimulants; however, the production and sale of stimulant drugs continued through criminal syndicates such as the Yakuza criminal organization. On the streets, it is also known as S, Shabu, and Speed, in addition to its old trademarked name.

In 1970, methamphetamine was regulated in the Controlled Substances Act in the U.S., and a public education campaign was mounted against it.

In the 1980s, drug treatment counselors saw increased abuse of the drug among men who have sex with men. Mexican drug manufacturers began bringing methamphetamine north of the border, and forms of methamphetamine that could be smoked are introduced.

In the 1990s, new ways to synthesize methamphetamine appeared. Some new versions were reported to be four to six times stronger. Greatest use was seen in the Southwest and West United States, but methamphetamine use began and grew in the rural Midwest. Rural locations become ideal for cooking of methamphetamine because of geographic isolation and an available supply of ephedrine, pseudoephedrine and anhydrous ammonia.

In 1996, Congress passed the Comprehensive Methamphetamine Control Act, which regulates mail order and chemical companies selling precursor chemicals. For example, people purchasing large quantities of red phosphorus, iodine and hydrochloric gas were required to document that they intended them for legitimate purposes. Law enforcement agents were allowed to track large mail order purchases of pseudoephedrine, another precursor chemical. Chemical supply companies could be prosecuted for selling chemicals to people who make methamphetamine.

By 2000, in the Inland Northwest, and in much of the West United States, methamphetamine was the favored hard drug, surpassing crack and cocaine as the stimulant of choice, as it offered 3.5 times more potency, and a much longer half life. Heroin use was also being surpassed with methamphetamine, which unlike heroin, is not severely cut and reduced in potency with other additive substances. The crystalline form of methamphetamine contained at least 80 percent purity.

Current status

Main article: Legal status of methamphetamine

The production, distribution, sale, and possession of methamphetamine is restricted or illegal in many jurisdictions. Methamphetamine has been placed in Schedule II of the United Nations Convention on Psychotropic Substances treaty.

United States

Anti-meth sign on tank of anhydrous ammonia (Otley, Iowa). Anhydrous ammonia is used in the production of farm fertilizer and is also a critical ingredient in making methamphetamine. In 2005, the state of Iowa gave out thousands of locks in order to prevent criminals from accessing the tanks.

In 1983, laws were passed in the United States prohibiting possession of precursors and equipment for methamphetamine production. This was followed a month later by a bill passed in Canada enacting similar laws. In 1986, the U.S. government passed the Federal Controlled Substance Analogue Enforcement Act in an attempt to curb the growing use of designer drugs. Despite this, use of methamphetamine expanded from its initial base in California throughout the rural United States, especially through the Midwest and South. "Government officials in a majority of U.S. counties now report that meth is their counties’ most serious drug problem. Meth use is said to be particularly rampant in the American western states, where the substance is in high demand. States like Montana, South Dakota, Idaho, Colorado and Arizona have all launched extensive efforts – both private and public – to fight the meth menace."

Since 1989, five U.S. federal laws and dozens of state laws have been imposed in an attempt to curb the production of methamphetamine. Methamphetamine can be produced in home laboratories using pseudoephedrine or ephedrine, which, at the time, were the active ingredients in over-the-counter drugs such as Sudafed and Contac. Preventive legal strategies of the past 17 years have steadily increased restrictions to the distribution of pseudoephedrine/ephedrine-containing products. As a result "pharmaceutical companies and retailers such as Target, Walgreens, CVS, Kroger and Winn-Dixie have restricted sales of pseudoephedrine-containing products. Purchasers have been limited to buying small quantities and required to show I.D. to purchase them."

Attorney General Janet Reno was very outspoken in warning mayors, police chiefs and the Judicial and Executive branches of the Federal government and as a Florida States' Attorney about the dangers of meth (-amphetamines) as early as 1996 and before. She was reported by the Orlando Sentinel as commenting that illegal trafficking in methamphetamine, a dangerous and powerful stimulant, had been spreading rapidly across the United States. She appeared at the 68th session of the United States Conference of Mayors Winter Meeting in Washington, D.C. in 2000 with President Clinton and others to discuss social and law enforcement dangers of the drug nationally, especially in medium-sized and rural communities in order to deal with "the rapidly emerging issue of meth in America, discuss the unique needs of smaller and mid-sized communities to deal with the crisis, and develop prevention, treatment and interdiction strategies for meth which can then be applied to cities of all sizes as the methamphetamine crisis spreads across the nation."

As a result of the U.S. Combat Methamphetamine Epidemic Act of 2005 (CMEA), which was passed as an amendment to the renewal of the USA PATRIOT Act, there are restrictions on the amount of pseudoephedrine and ephedrine one may purchase in a specified time period and further requirements that these products must be stored in order to prevent theft. "The CMEA requires record-keeping and identification of all sales and reports to law enforcement of any "suspicious" transactions. Purchasers are limited to "3.6 grams of pseudoephedrine base" per day and 9 grams per month. (Buying more than that is a federal misdemeanor.)" Increasingly strict restrictions have resulted in the reformulation of many over-the-counter drugs, and some, such as Actifed, have been discontinued entirely in the United States.

Meth lab waste is extremely hazardous and toxic. Waste cleanup is a major issue for authorities and property owners. Common wastes include brake cleaner, ammonia, soda bottles, kitty litter, lithium batteries, engine starter, matches, and pseudoephedrine blister packs.

North Korea

North Korea might also be facing one of the world's worst meth epidemics. Although the secrecy of the North means that any report may be only approximate, there have been an increasing number of signs that meth is very widespread throughout the country, used both recreationally and as medicine. Methamphetamine is called "bingdu" in North Korea.

Illicit production

Synthesis

Illicitly synthesized crystal methamphetamine

See also: Substituted amphetamine § Synthesis

Methamphetamine is most structurally similar to methcathinone and amphetamine. Synthesis is relatively simple, but entails risk with flammable and corrosive chemicals, particularly the solvents used in extraction and purification; therefore, illicit production is often discovered by fires and explosions caused by the improper handling of volatile or flammable solvents. The six major routes of production begin with either phenyl-2-propanone (P2P) or with one of the isomeric compounds pseudoephedrine and ephedrine.

Synthesis from phenyl-2-propanone and methylamine in the presence of aluminium amalgam

One procedure uses the reductive amination of phenyl-2-propanone (phenylacetone) with methylamine, P2P was usually obtained from phenylacetic acid and acetic anhydride, though many other methods have been considered, and phenylacetic acid might arise from benzaldehyde, benzylcyanide, or benzylchloride. Methylamine is crucial to all such methods, and is produced from the model airplane fuel nitromethane, or formaldehyde and ammonium chloride, or methyl iodide with hexamine. This was once the preferred method of production by motorcycle gangs in California, until DEA restrictions on the chemicals made the process difficult. Pseudoephedrine, ephedrine, phenylacetone, and phenylacetic acid are currently DEA list I and acetic anhydride is list II on the DEA list of chemicals subject to regulation and control measures. This method can involve the use of mercuric chloride and leaves behind mercury and lead environmental wastes. The methamphetamine produced by this method is racemic, consisting partly of the unsought levomethamphetamine isomer.

The alternative Leuckart route also relies on P2P to produce a racemic product, but proceeds via methylformamide in formic acid to an intermediate N-formyl-methamphetamine, which is then decarboxylated with hydrochloric acid.

Two infrequently used reductive amination routes have also been reported. The "nitropropene route", in which benzaldehyde is condensed with nitroethane to produce 1-phenyl-2-nitropropene, which is subsequently reduced by hydrogenation of the double bond and reduction of the nitro group using hydrogen over a palladium catalyst or lithium aluminum hydride. The "oxime route" reacts phenyl-2-propanol with hydroxylamine to produce an oxime intermediate which likewise is hydrogenated using hydrogen over a palladium catalyst or lithium aluminum hydride.

Illicit methamphetamine is more commonly made by the reduction of ephedrine or pseudoephedrine, which produces the more active d-methamphetamine isomer. The maximum conversion rate for ephedrine and pseudoephedrine is 92%, although typically, illicit methamphetamine laboratories convert at a rate of 50% to 75%. Most methods of illicit production involve protonation of the hydroxyl group on the ephedrine or pseudoephedrine molecule.

Reduction of ephedrine using hydrogen iodide in the presence of red phosphorus

Though dating back to the discovery of the drug, the Nagai route did not become popular among illicit manufacturers until ca. 1982, and comprised 20% of production in Michigan in 2002 It involves red phosphorus and hydrogen iodide (also known as hydroiodic acid or iohydroic acid). (The hydrogen iodide is replaced by iodine and water in the "Moscow route") The hydrogen iodide is used to reduce either ephedrine or pseudoephedrine to methamphetamine. On heating the precursor is rapidly iodinated by the hydrogen iodide to form iodoephedrine. The phosphorus assists in the second step, by consuming iodine to form phosphorus triiodide (which decomposes in water to phosphorous acid, regenerating hydrogen iodide). Because hydrogen iodide exists in a chemical equilibrium with iodine and hydrogen, the phosphorus reaction shifts the balance toward hydrogen production when iodine is consumed. In Australia, criminal groups have been known to substitute "red" phosphorus with either hypophosphorous acid or phosphorous acid (the "Hypo route"). This is a hazardous process for amateur chemists because phosphine gas, a side-product from in situ hydrogen iodide production, is extremely toxic to inhale. The reaction can also create toxic, flammable white phosphorus waste. Methamphetamine produced in this way is usually more than 95% pure.

Thionyl chloride synthesis

The conceptually similar Emde route involves reduction of ephedrine to chloroephedrine using thionyl chloride (SOCl₂), followed by catalytic hydrogenation. The catalysts for this reaction are palladium or platinum. The Rosenmund route also uses hydrogen gas and a palladium catalyst poisoned with barium sulfate (Rosenmund reduction), but uses perchloric acid instead of thionyl chloride.

The Birch reduction, also called the "Nazi method", became popular in the mid-to-late 1990s and comprised the bulk of methamphetamine production in Michigan in 2002. It reacts pseudoephedrine with liquid anhydrous ammonia and an alkali metal such as sodium or lithium. The reaction is allowed to stand until the ammonia evaporates. However, the Birch reduction is dangerous because the alkali metal and ammonia are both extremely reactive, and the temperature of liquid ammonia makes it susceptible to explosive boiling when reactants are added. It has been the most popular method in Midwestern states of the U.S. because of the ready availability of liquid ammonia fertilizer in farming regions.

In recent years, a simplified "Shake 'n Bake" one-pot synthesis has become more popular. The method is suitable for such small batches that pseudoephedrine restrictions are less effective, it uses chemicals that are easier to obtain (though no less dangerous than traditional methods), and it is so easy to carry out that some addicts have made the drug while driving. It involves placing crushed pseudoephedrine tablets into a nonpressurized container containing ammonium nitrate, water, and a hydrophobic solvent such as Coleman fuel or automotive starting fluid, to which lye and lithium (from lithium batteries) is added. Hydrogen chloride gas produced by a reaction of salt with sulfuric acid is then used to recover crystals for purification. The container needs to be "burped" periodically to prevent failure under accumulating pressure, as exposure of the lithium to the air can spark a flash fire; thus an abandoned reaction becomes a severe hazard to firefighters. The battery lithium can react with water to shatter a container and potentially start a fire or explosion.

Producing methamphetamine in this fashion can be extremely dangerous and has been linked to several fatalities. Because users frequently carry out the reaction in a two-liter bottle held close to their bodies, which can explode if the cap is removed too soon or if it accidentally perforates, the procedure has led to a large number of severe burns - for example, approximately 70 in Indiana during 2010 and 2011. As 90% of these cases in the United States lack health insurance, and the average cost for their treatment is $130,000 (60% more than the average), which is only partially compensated by Medicaid, this method of synthesis has been blamed for the closure of hospital burn units and a cost to taxpayers of tens or hundreds of millions of dollars.

Production and distribution

See also: Illegal drug trade

Illicit industrial-scale methamphetamine and MDMA chemical factory (Cikande, Indonesia)

1 lb (454 g) of methamphetamine found on a passenger at LA International Airport (LAX)

Until the early 1990s, methamphetamine for the U.S. market was made mostly in labs run by drug traffickers in Mexico and California. Indiana state police found 1,260 labs in 2003, compared to just 6 in 1995, although this may be partly a result of increased police activity. As of 2007, drug and lab seizure data suggests that approximately 80 percent of the methamphetamine used in the United States originates from larger laboratories operated by Mexican-based syndicates on both sides of the border and that approximately 20 percent comes from small toxic labs (STLs) in the United States.

Mobile and motel-based methamphetamine labs have caught the attention of both the U.S. news media and the police. Such labs can cause explosions and fires and expose the public to hazardous chemicals. Those who manufacture methamphetamine are often harmed by toxic gases. Many police departments have specialized task forces with training to respond to cases of methamphetamine production. The National Drug Threat Assessment 2006, produced by the Department of Justice, found "decreased domestic methamphetamine production in both small and large-scale laboratories", but also that "decreases in domestic methamphetamine production have been offset by increased production in Mexico." The report concluded that "methamphetamine availability is not likely to decline in the near term."

Methamphetamine labs can give off noxious fumes, such as phosphine gas, methylamine gas, solvent vapors, acetone or chloroform, iodine vapors, white phosphorus, anhydrous ammonia, hydrogen chloride/muriatic acid, hydrogen iodide, lithium and sodium gases, ether, or methamphetamine vapors. If performed by amateurs, manufacturing methamphetamine can be extremely dangerous. If the red phosphorus overheats, because of a lack of ventilation, phosphine gas can be produced. This gas is highly toxic and, if present in large quantities, is likely to explode upon autoignition from diphosphine, which is formed by overheating phosphorus.

In July 2007, Mexican officials at the port of Lázaro Cárdenas seized a ship carrying 19 tons of pseudoephedrine, a raw material needed for methamphetamine. The shipment originated in Hong Kong and passed through the United States at the port of Long Beach prior to its arrival in Mexico.

Impurities and adulterants

In Japan, methamphetamine seizures are usually white crystals of high purity, but contain impurities that vary according to the means of production, and are sometimes adulterated.

Diagnostic impurities are the napthalenes 1-benzyl-methylnaphthalene and 1,3-dimethyl-2-phenylnaphthalene, arising in the Nagai and Leuckart routes, and cis- or trans- 1,2-dimethyl-3-phenylaziridine, ephedrine, or erythro-3,4-dimethyl- 5-phenyloxazolidine, arising in the Nagai and Emde routes; these are absent in the reductive amination route. Characteristic impurities of the Birch route include N-methyl-1-(1-(1,4-cyclohexadienyl))-2-propanamine. Methamphetamine produced by the Birch route contains phenyl-2-propanone, the precursor for the reduc PARTY HARD AND ROCK AND ROLL!

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Notes

• Yudko, Errol (2008-10-29). Methamphetamine Use: Clinical and Forensic Aspects. 408 (2nd ed.). Boca Raton, FL: CRC Press. ISBN 978-0-8493-7273-5. {{cite book}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

External links

• NLM Hazardous Substances Data Bank—Entry for d-methamphetamine
• Desoxyn—Prescription form of the drug.
• EMCDDA drugs profiles: Methamphetamine (2007)
• EMCDDA paper on Methamphetamine supply in Europe (2009)
• A Key to Methamphetamine-Related Literature—A comprehensive thematic index of methamphetamine research published in academic and scientific journals with links from citations to the PubMed abstracts.
• DEA's Methamphetamine News Releases
• Poison Information Monograph (PIM 334: Methamphetamine)
• Chronic Amphetamine Use and Abuse—A thorough review on the effects of chronic use (American College of Neuropsychopharmacology)
• U.S. National Library of Medicine: Drug Information Portal - Methamphetamine
• ChemSub Online: Methamphetamine

Documentaries

• The Ice Age by ABC Australia—Australian methamphetamine use.
• The Meth Epidemic—Frontline episode
• The World's Most Dangerous Drug—National Geographic.
• The City Addicted to Crystal Meth—BBC (Louis Theroux)

Academic sources

• History and Epidemiology of Amphetamine Abuse in United States
• Methamphetamine, the Crystal Method, and the War on Drugs
• The Methamphetamine Crisis in American Indian and Native Alaskan Communities