Drugs & Medication

Methamphetamine
Systematic (IUPAC) name
(S)-N-methyl-1-phenyl-propan-2-amine
Identifiers
CAS number	537-46-2
ATC code	N06BA03
PubChem	1206
Chemical data
Formula	C10H15N
Mol. weight	149.2 g/mol
Pharmacokinetic data
Bioavailability	Depends on route of administration
Metabolism	Hepatic
Half life	9-15 hours[1]
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	C(US)
Legal status	Schedule I(CA) Schedule II(US) Class A(NZ) Schedule 5(SA) Injectable:Class A, Oral: B(UK)
Routes	Medical: Oral Recreational: Oral, I.V., I.M., Insufflation, Inhalation, Suppository

Methamphetamine (sometimes referred to as methylamphetamine or desoxyephedrine) is a psychostimulant drug used primarily for recreational purposes, but is sometimes prescribed for ADHD and narcolepsy under the brand name Desoxyn. It causes euphoria and excitement by acting directly on the brain's reward mechanisms, thus making it highly addictive. Methamphetamine rapidly enters the brain and causes a cascading release of norepinephrine and dopamine (and to a lesser extent, serotonin). Users may become obsessed or perform repetitive tasks such as cleaning, hand-washing or assembling and disassembling objects.^[2] Withdrawal is characterized by increased sleeping and eating, and depression-like symptoms, often accompanied by anxiety and drug-craving.^[3]

Contents 1 Availability and names 2 History 3 Production 4 Distribution 5 Medical use 6 Pharmacology 6.1 Tolerance 7 Side effects 8 Addiction 9 Routes of administration 10 Legality 10.1 Australia 10.2 Canada 10.3 New Zealand 10.4 South Africa 10.5 United Kingdom 10.6 United States 11 See also 12 References 13 Footnotes 14 External links

Availability and names

In the U.S., illicit methamphetamine comes in a variety of forms, with an average price of $150 per gram of pure substance.^[4] Most commonly it is found as a colorless crystalline solid, sold on the street under the name crystal meth and a variety of other names. It is also sold as a less pure crystalline powder called crank, or in crystalline rock form. Colourful flavored pills containing methamphetamine and caffeine are known as yaba (Thai for "crazy medicine"). At its most impure, it is sold as a crumbly brown or off-white rock commonly referred to as "peanut butter crank"[5]. Methamphetamine found on the street is rarely pure, but adulterated with chemicals that were used to synthesize it. It may be diluted or "cut" with non-psychoactive substances like inositol. It may also be cut with other psychoactive substances, but the reverse is presumably more common due to its low price relative to other common drugs.

History

Methamphetamine was first synthesized from ephedrine in Japan in 1893 by chemist Nagayoshi Nagai. In 1919, crystallized methamphetamine was synthesized by Akira Ogata via reduction of ephedrine using red phosphorus and iodine. The related compound amphetamine was first synthesized in Germany in 1887 by Lazar Edeleanu.

One of the earliest uses of amphetamine occurred during World War II when the German military dispensed the stimulant under the trade name Pervitin to troops.^[6] The drug was widely distributed across rank and division, from elite forces to tank crews and aircraft personnel. Chocolates dosed with methamphetamine were known as Fliegerschokolade ("flyer's chocolate") when given to pilots, or Panzerschokolade ("tanker's chocolate") when distributed to tank crews.

Adolf Hitler is rumored to have received three daily IV injections of amphetamines and steroids from his personal physician, Theodore Morell. After World War II, a massive supply of amphetamine, formerly stockpiled by the Japanese military, became available in Japan under the street name shabu (also Philopon (pronounced ヒロポン, or Hiropon), its tradename there.[7]) The Japanese Ministry of Health banned it in 1951, which is thought to have added to the growing yakuza activities related to illicit drug production.^[8] Today, the Japanese underworld is still associated with the drug, although its use is discouraged by strong social taboos.

With the 1950s came a rise in the legal prescription of methamphetamine to the American public. According to the 1951 edition of Pharmacology and Therapeutics (by Arthur Grollman), it was to be prescribed for "narcolepsy, post-encephalitic parkinsonism, alcoholism, ... in certain depressive states... and in the treatment of obesity."

The 1960s saw the start of the significant use of clandestine manufacture to supply methamphetamine. Prior to 1983, U.S. laws prohibiting the possession of precursors and equipment for methamphetamine production were not yet in place. The recreational use of Levoamphetamine sky-rocketed in the 1980s. The December 2, 1989 edition of The Economist described San Diego, California as the "methamphetamine capital of North America."

In 1986, the U.S. government passed the Federal Controlled Substance Analogue Enforcement Act in an attempt to combat the growing use of designer drugs. In spite of this, its use expanded throughout the rural United States, especially in the Midwest and South. Growth of methamphetamine use continues into the 21st century, and many states are considering tougher legislation.

On August 8, 2005, an issue of Newsweek devoted a cover story to methamphetamine and its abuse,[9] including criticism of the Bush administration's policies regarding meth. Newsweek blamed the administration for not devoting enough resources to education about and prevention of the drug's use. The Bush administration has countered with the position that cannabis is a dangerous 'gateway drug', so prevention of cannabis use should prevent potential abusers from trying and becoming hooked on "hard" drugs such as methamphetamine.

Meanwhile, the online magazine Slate posted an article in reaction to the Newsweek article,^[10] attacking Newsweek for failing to appropriately cite sources and data to back up the claim that this is a "new" problem. The topic remains controversial. The most recent figures released by the Federal government indicate that contrary to public perception, methamphetamine use has actually declined nationally in recent years.^[11]

Production

Methamphetamine is most structurally similar to methcathinone and amphetamine. In illicit production, it is commonly made by the reduction of ephedrine or pseudoephedrine. Most of the necessary chemicals are readily available in household products or over-the- counter medicines. Synthesis is relatively simple, but most methods involve flammable and corrosive chemicals. As a result, clandestine production is often discovered due to fires caused by amateur chemists working with makeshift laboratory equipment.

Most production methods involve hydrogenation of the hydroxyl group on the ephedrine/pseudoephedrine molecule. The most common method in the United States involves red phosphorus and iodine which forms hydroiodic acid. This is a fairly dangerous process; in fact, on the Darwin Awards site, there is a story of a man who burned himself trying to conceal these chemicals.[12] The red phosphorus production method can create phosphine gas, which is extremely toxic when inhaled. An increasingly common method utilizes a Birch reduction process, where metallic lithium is substituted for metallic sodium (due to the difficulty in obtaining metallic sodium). The Birch reduction is dangerous since the alkali metal and liquid anhydrous ammonia are both extremely reactive, and because the temperature of liquid ammonia makes it susceptible to explosive boiling when reactants are added.

Other less-common methods use other means of hydrogenation, such as hydrogen gas in the presence of a catalyst.

A completely different synthesis procedure involves creating methamphetamine by the reductive amination of phenylacetone with methylamine, both of which are currently DEA list I chemicals (as are pseudoephedrine and ephedrine). This was once the preferred method of production by motorcycle gangs in California, but DEA restrictions on the chemicals have made this an uncommon way to produce the drug today.

One of the more obvious signs of a production lab of metamphetamine in operation is the smell of a cat-urine-like odor.

When performed by individuals who are not trained chemists, methamphetamine manufacture can lead to extremely dangerous situations. For example, if the red phosphorus reaction is allowed to overheat, phosphine gas can be produced. When produced in large quantities, it usually explodes, due to autoignition from diphosphine formation caused by overheating phosphorus.

Until the early 1990s, methamphetamine for the US market was made mostly in clandestine labs run by drug traffickers in Mexico and California. These areas are still the largest producers for the U.S. market. Since then, however, authorities have discovered increasing numbers of small-scale methamphetamine labs all over the United States, mostly located in rural, suburban, or low-income areas. The Indiana state police found 1,260 labs in 2003, compared to just 6 in 1995, although this may only be a result of increased police activity.^[13]

Recently, mobile and motel-based methamphetamine labs have caught the attention of both the US news media and law enforcement agencies. The labs can cause explosions and fires, as well as expose the public to hazardous chemicals. In addition to these issues, individuals who manufacture methamphetamine are often harmed by toxic gases. Many police forces have responded by creating a specialized task force educated in responding to persons involved in methamphetamine production.

The amount of methamphetamine actually contributed to the US market by small-scale labs is disputed. Large-scale labs maintained by criminal organizations continue to exist. In the United States, Drug policy critics suggest that restriction of over-the-counter medication is more politically than socially motivated, and may in fact shift the balance of supply more in favor of large criminal organizations.

Distribution

A wide variety of groups are involved in the distribution of methamphetamine, from the aforementioned prison gangs and motorcycle gangs to street gangs, traditional organized crime operations, and impromptu small networks made up of users. The government of North Korea has been linked to the manufacture and distribution of crystal meth, and allegedly plays a role in distribution networks throughout Asia as well as those in Australia and even in North America [14]. Regardless, meth trafficking is not exclusively dominated by cartels along the lines of Colombian cocaine cartels or Pakistani heroin cartels.

Medical use

• Attention deficit hyperactivity disorder
  Narcolepsy
  Extreme obesity
  Severe depression
• Decongestant

Pharmacology

Methamphetamine is a potent central nervous system stimulant which affects neurochemical mechanisms responsible for regulating heart rate, body temperature, blood pressure, appetite, attention, mood and responses associated with alertness or alarm conditions. Methamphetamine causes the norepinephrine transporter, dopamine transporter 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, 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. Serotonin levels are only weakly affected (ratio NE: DA = 2:1, NE:5HT = 60:1).^[15] It is neurotoxic in overdose.^[16]

The acute 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.

L-methamphetamine (also called levmetamfetamine and desoxyephedrine) has nasal decongestant activity and no abuse potential. This is the active ingredient in the US Vicks Inhaler.

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 varies widely between individuals, and even within one individual it is highly dependant on dosage, duration of use and frequency of administration. Many cases of narcolepsy are treated with methamphetamine for years without escalating doses or any apparent loss of effect.

Short term tolerance can be caused by depleted levels of neurotransmitters within the vesicles available for release into the synaptic cleft following subsequent reuse (tachyphylaxis). Short term tolerance typically lasts 2-3 days, until neurotransmitter levels are fully replenished. 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.^[17] To compensate, larger quantities of the drug are needed in order to achieve the same level of effects.

Side effects

The most common side effects include twitching, "jitteriness", repetitive behavior (known as "tweaking"), and jaw clenching or teeth grinding.

Methamphetamine addicts may lose their teeth abnormally fast, a condition known as "meth mouth". Similar, though far less severe symptoms have been reported in clinical use of other amphetamines, where effects are not exacerbated by a lack of oral hygiene for extended periods.^[18] Like other substances which stimulate the sympathetic nervous system, methamphetamine causes decreased production of acid-fighting saliva and increased thirst, resulting in increased risk for tooth decay, especially when thirst is quenched by high-sugar drinks.^[19]

Users may exhibit sexually compulsive behavior and may engage in sexual acts with one or more individuals. This sexual behavior is believed to have created a link between meth use and sexually transmitted disease (STD) transmission, especially HIV and syphilis. This caused great concern among larger gay communities, particularly those in Atlanta, Miami, Chicago, New York City, and San Francisco, leading to outreach programs and rapid growth in 12-step organizations such as Crystal Meth Anonymous.

Common side effects:^[20]

• Diarrhea, nausea
• Loss of appetite, insomnia, tremor, jaw-clenching
• Agitation, compulsive fascination with repetitive tasks (Punding)
• Talkativeness, irritability, panic attacks
• Increased libido
• Dilated pupils

Side effects associated with chronic use:

• Drug craving
• Weight loss
• Withdrawal-related depression and anhedonia
• Erectile dysfunction ("Crystal cock")
• Rapid tooth decay ("meth mouth")
• Amphetamine psychosis

Side effects associated with overdose:

• Formication (sensation of flesh crawling with bugs, with possible associated compulsive picking and infecting sores "Meth Mites")
• Brain damage (Neurotoxicity)
• Paranoia, delusions, hallucinations
• Kidney damage (from Hyperkalemia)

Overdose fatalities are usually due to stroke or heart failure, but can also be caused by hyperthermia or kidney failure.

Addiction

Methamphetamine is highly addictive, particularly when injected or smoked.^[21] While not life-threatening, withdrawal is often intense and, as with all addictions, relapse is common. To combat relapse, many recovering addicts attend 12 Step meetings, such as Crystal Meth Anonymous.

In an article about his son's addiction to methamphetamine, a California writer who has also experimented with the drug put it this way:

[T]his drug has a unique, horrific quality. In an interview, Stephan Jenkins, the singer in the band Third Eye Blind, said that methamphetamine makes you feel 'bright and shiny.' It also makes you paranoid, incoherent and both destructive and pathetically and relentlessly self-destructive. Then you will do unconscionable things in order to feel bright and shiny again.^[22]

Former users have noted that they feel stupid or dull when they quit using methamphetamine. This is because the brain is adapting a need for methamphetamine to think faster, or at what seems to be a higher level. Individuals with ADHD may be at higher risk for addiction to methamphetamine, because the drug increases the user's ability to focus and reduces impulsivity. Because of its abuse potential, meth is not generally prescribed for ADHD unless other stimulants, such as methylphenidate (Ritalin®), dextroamphetamine (Dexedrine®) or mixed amphetamines (Adderall®) have failed.

With long-term use, abstinence often leads to slow thinking and depression, which in turn requires that the addict use more meth to 'fix' it. A chronic pattern of such behavior is known colloquially as "The Vampire Life."

Serious drug addiction correlates with poor hygiene and general self-care, and even minor health problems can lead to serious complications when left untreated. Striking health problems popularly associated with methamphetamine addiction, such as severe tooth decay or massive skin infections, are caused by unsterilized needles and a lack of hygiene. Even long-term use does not generally result in outward symptoms, but may lead to hypertension, damage to heart valves, and increased risk of strokes.

Routes of administration

The usual route for medical use is oral administration. In recreational use it can be swallowed, snorted, smoked, dissolved in water and injected (or even without water, in what is called a dry shot), inserted anally (with or without dissolution in water), or into the urethra. ^[23] As with all addictive drugs, the potential for addiction is greater when it is delivered by methods that cause the concentration in the blood to rise quickly, principally because the effects desired by the user are felt more quickly and with a higher intensity than through a moderated delivery mechanism. In fact, studies have shown that the subjective pleasure of drug use (the reinforcing component of addiction) is proportional to the rate that the blood level of the drug increases. In general, smoking is the fastest mechanism (i.e., it causes the blood concentration to rise the most quickly in the shortest period of time as it allows the substance to travel to the brain through a more direct route than intravenous injection), followed by injecting, snorting, anal insertion, and swallowing.

"Smoking" methamphetamine actually refers to vaporizing it to produce fumes, rather than burning and inhaling the resulting smoke, as with tobacco. It is commonly smoked in glass pipes, or in aluminum foil heated by a flame underneath. This method is also known as "chasing the white dragon" (as derived from the method of smoking opium 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 and associated complications), or limited to injection users (pulmonary emboli).

Injection is a popular method for use, but potentially carries quite serious risks. The hydrochloride salt of methamphetamine is soluble in water; injection users may use any dose from 125 mg to over a gram in one I.V. dose using a small needle. This dosage range may be fatal to non-addicts; addicts rapidly develop tolerance to the drug. Injection users often experience skin rashes (sometimes called "speed bumps") and infections at the site of injection. As with any injected drug, if a group of users shares a common needle or any type of injecting equipment without sterilization procedures, blood-borne diseases such as HIV or hepatitis can be transmitted as well.

Very little research has focused on anal insertion as a method, and anecdotal evidence of its effects is infrequently discussed, possibly due to social taboos in many cultures regarding the anus. This is often known within communities that use meth for sexual stimulation as a "booty bump" or "Keistering," and is anecdotally reported to increase sexual pleasure while the effects of the drug last.^[24] The rectum is where the majority of the drug would likely be taken up, through the mucous membranes lining its walls.

Legality

See pseudoephedrine, for legal restrictions placed on that drug as a result of its use as a precursor in the clandestine manufacture of methamphetamine.

Australia

The medical use of methamphetamine is not recognised in Australia and as such it is outlawed.

Canada

Methamphetamine is not approved for medical use in Canada. As of 2005, it falls under Schedule I of the Controlled Drugs and Substances Act. The maximum penalty for the production and distribution is imprisonment for life.

New Zealand

Methamphetamine is a Class A controlled drug under the New Zealand Misuse of Drugs Act 1975. The maximum penalty for production and distribution is imprisonment for life. The maximum penalty for possession is imprisonment for six months. The NZ Misuse of Drugs Act 1975 also covers a "presumption amount". This refers to the quantity of drug that is in a person's possession. If a person is caught with more than a certain amount, it is assumed that the person is in possession of that drug for the purpose of supplying it.

South Africa

In South Africa, methamphetamine is classified as a Schedule 5 drug, and is listed as Undesirable Dependence-Producing Substances in Part III of Schedule 2 of the Drugs and Drug Trafficking Act, 1992 (Act No 140 of 1992).^[25] Commonly called "tik", it is mostly abused by youths under the age of 20 in the Cape Flats areas.

United Kingdom

In the UK, methamphetamine was classified as a Class B drug under the Misuse of Drugs Act 1971. The maximum penalty for possession is five years imprisonment, and the maximum penalty for supplying is 14 years. If methamphetamine (or any other Class B drug) is prepared for injection, then it is re-classified as a Class A drug. The maximum penalty for such possession is seven years imprisonment, and the maximum penalty for supplying is life imprisonment.

In 2006, it was announced that methamphetamine is to be reclassified as a Class A drug and has been reclassed as such, following a recommendation made by the Advisory Council on the Misuse of Drugs.^[26]

United States

Methamphetamine is classified as a Schedule II substance by the Drug Enforcement Administration under the Convention on Psychotropic Substances.^[27] While there is technically no difference between the laws regarding methamphetamine and other controlled stimulants, most medical professionals are averse to prescribing it due to its notoriety.

Methamphetamine is legally marketed in the United States under the trade name Desoxyn, manufactured by Ovation Pharma. Generic formulations of the drug are also available.

Methamphetamine has become a major focus of the 'war on drugs' in the US in recent years. In some areas of the United States, manufacturing methamphetamine is punishable by a mandatory ten-year prison sentence. In certain instances, however, judges have ruled for life in prison without the possibility of parole, especially in cases where victims were killed by overdoses or impure substances. Crackdowns on the theft of anhydrous ammonia, a substance used in the manufacture of the drug, have resulted in additional prison time.

See also

• Amphetamine
• Phenethylamines

References

• Poison Information Monograph (PIM 334: Methamphetamine)
• NIH Hazardous Substances Data Bank - Entry for d-methamphetamine
• Chronic Amphetamine Use and Abuse A very thorough review on the effects of chronic use (American College of Neuropsychopharmacology)
• Methamphetamine Use: Clinical and Forensic Aspects, by Errol Yudko, Harold V. Hall, and Sandra B. McPherson. CRC Press, Boca Raton, Fl, 2003.

Footnotes

External links

• Asia & Pacific Amphetamine-Type Stimulants Information Centre