Methamphetamine

Methamphetamine (pronunciation: /ˌmɛθæmˈfɛtəmiːn/; contracted from N-methyl-alpha-methylphenethylamine) is a potent central nervous system (CNS) stimulant of the phenethylamine and amphetamine classes that is used as a recreational drug and, rarely, to treat attention deficit hyperactivity disorder (ADHD) and obesity. Methamphetamine exists as two enantiomers, dextrorotary and levorotary. Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine; however, both are neurotoxic, addictive and produce the same toxicity symptoms at high doses. Although rarely prescribed due to the potential risks, methamphetamine hydrochloride is approved by the United States Food and Drug Administration (USFDA) under the trade name Desoxyn. Recreationally, methamphetamine is used to increase sexual desire, lift the mood, and increase energy, allowing some users to engage in sexual activity continuously for several days straight.

Methamphetamine may be sold illegally, either as pure dextromethamphetamine or in an equal parts mixture of the right and left handed molecules (i.e., 50% levomethamphetamine and 50% dextromethamphetamine). Both dextromethamphetamine and racemic methamphetamine are schedule II controlled substances in the United States. Similarly, the production, distribution, sale, and possession of methamphetamine is restricted or illegal in many other countries due to its placement in schedule II of the United Nations Convention on Psychotropic Substances treaty. In contrast, levomethamphetamine is an over-the-counter drug in the United States.

In low doses, methamphetamine can cause an elevated mood and increase alertness, concentration, and energy in fatigued individuals. At higher doses, it can induce psychosis, rhabdomyolysis and cerebral hemorrhage. Methamphetamine is known to have a high potential for abuse and addiction. Heavy recreational use of methamphetamine may result in psychosis or lead to post-acute-withdrawal syndrome, a withdrawal syndrome that can persist for months beyond the typical withdrawal period.^[i] Unlike amphetamine, methamphetamine is neurotoxic to humans, damaging both dopamine and serotonin neurons in the CNS.^[i] Contrary to the long-term use of amphetamine,^[iii] there is evidence that methamphetamine causes brain damage from long-term use in humans;^[ii] this damage includes adverse changes in brain structure and function, such as reductions in gray matter volume in several brain regions and adverse changes in markers of metabolic integrity.^[ii]

Uses

Medical

In the United States, methamphetamine hydrochloride, under the trade name Desoxyn, has been approved by the FDA for treating ADHD and exogenous obesity (obesity originating from factors outside the patient's control) in both adults and children; however, the FDA also indicates that the limited therapeutic usefulness of methamphetamine should be weighed against the inherent risks associated with its use. Methamphetamine has also been prescribed off-label for narcolepsy infrequently in the past. In the United States, methamphetamine's levorotary form is available in some over-the-counter nasal decongestant products, such as Vicks VapoInhaler.

As methamphetamine is associated with a high potential for misuse, the drug is regulated under the Controlled Substances Act and is listed under schedule II in the United States. Methamphetamine hydrochloride dispensed in the United States is required to include the following boxed warning:

Recreational

Methamphetamine is often used recreationally for its effects as a potent euphoriant and stimulant as well as aphrodisiac qualities. According to a National Geographic TV documentary on methamphetamine, "an entire subculture known as party and play is based around methamphetamine use". Members of this San Francisco sub-culture, which consists almost entirely of gay male methamphetamine users, will typically meet up through internet dating sites and have sex. Due to its strong stimulant and aphrodisiac effects and inhibitory effect on ejaculation, with repeated use, these sexual encounters will sometimes occur continuously for several days. The crash following the use of methamphetamine in this manner is very often severe, with marked hypersomnia.

Contraindications

Methamphetamine is contraindicated in individuals with a history of drug abuse, heart disease, or severe agitation or anxiety, or in individuals currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension. The USFDA 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. The USFDA 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. Due to the potential for stunted growth, the USFDA advises monitoring the height and weight of growing children and adolescents during treatment.

Side effects

Physical

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. Methamphetamine that is present in a mother's bloodstream can pass through the placenta to a fetus and is or be 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 fast breathing. This withdrawal syndrome is relatively mild and only requires medical intervention in approximately 4% of cases.

Meth mouth

Methamphetamine users and addicts may lose their teeth abnormally quickly, regardless of the route of administration, from a condition informally known as meth mouth. The condition is generally most severe in users who inject the drug, rather than those who smoke, ingest, or inhale it. 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)". Many researchers suggest that methamphetamine-induced tooth decay is due to users' lifestyles, as dry mouth is also a side effect of other stimulants, which aren't known to cause serious tooth decay. They suggest that the side effect has been exaggerated and stylized to deter potential users and stereotype current users.

Psychological

The psychological effects of methamphetamine can include euphoria, dysphoria, changes in libido, alertness, apprehension, concentration, decreased sense of fatigue, insomnia or wakefulness, self-confidence, sociability, irritability, restlessness, grandiosity and repetitive and obsessive behaviors. Methamphetamine use also has a high association with anxiety, depression, methamphetamine psychosis, suicide, and violent behaviors. Methamphetamine also has a very high addiction risk.

Dependence, addiction, and withdrawal

Tolerance is expected to develop with regular methamphetamine use and, when abused, this tolerance develops rapidly.

The evidence on effective treatments for amphetamine and methamphetamine dependence and abuse is limited. In light of this, fluoxetine and imipramine appear to have some limited benefits in treating abuse and addiction, "no treatment has been demonstrated to be effective for the treatment of [methamphetamine] dependence and abuse".

In highly dependent amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue [methamphetamine] use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose". Withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for three to four weeks with a marked "crash" phase occurring during the first week. Methamphetamine withdrawal symptoms can include anxiety, drug craving, dysphoric mood, fatigue, increased appetite, increased movement or decreased movement, lack of motivation, sleeplessness or sleepiness, and vivid or lucid dreams. Withdrawal symptoms are associated with the degree of dependence (i.e., the extent of abuse). The mental depression associated with methamphetamine withdrawal lasts longer and is more severe than that of cocaine withdrawal.

Current models of addiction from chronic drug use involve alterations in gene expression in certain parts of the brain. The most important transcription factors that produce these alterations are Î"FosB, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), and nuclear factor kappa B (NFκB). Î"FosB is the most significant, since its overexpression in the nucleus accumbens is necessary and sufficient for many of the neural adaptations seen in drug addiction; it has been implicated in addictions to alcohol, cannabinoids, cocaine, nicotine, phencyclidine, and substituted amphetamines. Î"JunD is the transcription factor which directly opposes Î"FosB. Increases in nucleus accumbens Î"JunD expression can reduce or, with a large increase, even block most of the neural alterations seen in chronic drug abuse (i.e., the alterations mediated by Î"FosB). Î"FosB also plays an important role in regulating behavioral responses to natural rewards, such as palatable food, sex, and exercise. Since natural rewards, like drugs of abuse, induce Î"FosB, chronic acquisition of these rewards can result in a similar pathological addictive state. Consequently, Î"FosB is the key transcription factor involved in methamphetamine addiction, especially methamphetamine-induced sex addictions. Î"FosB inhibitors (drugs that oppose its action) may be an effective treatment for addiction and addictive disorders.

Neurotoxicity

Unlike amphetamine, methamphetamine is directly neurotoxic to dopamine neurons. Moreover, methamphetamine abuse is associated with an increased risk of Parkinson's disease due to excessive pre-synaptic dopamine autoxidation, a mechanism of neurotoxicity. Similar to the neurotoxic effects on the dopamine system, methamphetamine can also result in neurotoxicity to serotonin neurons. It has been demonstrated that a high core temperature is correlated with an increase in the neurotoxic effects of methamphetamine. As a result of methamphetamine-induced neurotoxicity to dopamine neurons, chronic use may also lead to Post-acute-withdrawals which persist beyond the withdrawal period for months, and even up to a year.

Sexually transmitted disease

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. 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. 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. Methamphetamine may also cause sores and abrasions in the mouth via bruxism, increasing the risk of sexually transmitted infection.

Besides the sexual transmission of HIV, it may also be transmitted between users who share a common needle. The level of needle sharing among methamphetamine users is similar to that among other drug injection users.

Overdose

A methamphetamine overdose may result in a wide range of symptoms. A moderate overdose of methamphetamine may induce symptoms such as: abnormal heart rhythm, confusion, difficult and/or painful urination, high or low blood pressure, high body temperature, over-active and/or over-responsive reflexes, muscle aches, severe agitation, rapid breathing, tremor, urinary hesitancy, and an inability to pass urine. An extremely large overdose may produce symptoms such as adrenergic storm, methamphetamine psychosis, substantially reduced or nil urine output, cardiogenic shock, brain bleed, circulatory collapse, dangerously high body temperature, pulmonary hypertension, kidney failure, rhabdomyolysis, serotonin syndrome, and a form of stereotypy ("tweaking"). A methamphetamine overdose will likely also result in mild brain damage due to dopaminergic and serotonergic neurotoxicity. Death from methamphetamine poisoning is typically preceded by convulsions and coma.

Emergency treatment

The USFDA states that acute methamphetamine intoxication is largely managed by treating the symptoms and includes may initially include administration of activated charcoal and sedation. There is not enough evidence on hemodialysis or peritoneal dialysis in cases of methamphetamine intoxication to determine their usefulness. 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. Hypertension presents a risk for intracranial hemorrhage and, if severe, is typically treated with Intravenous (IV) phentolamine or nitroprusside. Blood pressure often drops gradually following sufficient sedation with a benzodiazepine and providing a calming environment. Chlorpromazine may be useful in decreasing the stimulant and CNS effects of a methamphetamine overdose. The use of a nonselective beta blocker may be required to control increased heart rate.

Psychosis

Abuse of methamphetamine can result in a stimulant psychosis which may present with a variety of symptoms (e.g. paranoia, hallucinations, delirium, delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5â€"15% of users fail to recover completely. The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Methamphetamine psychosis may also develop occasionally as a treatment-emergent side effect.

Interactions

Methamphetamine is metabolized by the liver enzyme CYP2D6, so CYP2D6 inhibitors (e.g., selective serotonin reuptake inhibitors (SSRIs)) will prolong the elimination half-life of methamphetamine. Methamphetamine also interacts with monoamine oxidase inhibitors (MAOIs), since both MAOIs and methamphetamine increase plasma catecholamines; therefore, concurrent use of both is dangerous. Methamphetamine may decrease the effects of sedatives and depressants and increase the effects of antidepressants and other stimulants as well. Methamphetamine may counteract the effects of antihypertensives and antipsychotics due to its effects on the cardiovascular system and cognition respectively. The pH of gastrointestinal content and urine affects the absorption and excretion of methamphetamine. Specifically, acidic substances will reduce the absorption of methamphetamine and increase urinary excretion, while alkaline substances do the opposite. Due to the effect pH has on absorption, proton pump inhibitors, which reduce gastric acid, are known to interact with methamphetamine.

Pharmacology

Pharmacodynamics

Like amphetamine, methamphetamine has been identified as a potent full agonist of trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor (GPCR) that regulates brain catecholamine systems. Activation of TAAR1, via adenylyl cyclase, increases cyclic adenosine monophosphate (cAMP) production and either completely inhibits or reverses the transport direction of the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT). When methamphetamine binds to TAAR1, it triggers transporter phosphorylation via protein kinase A (PKA) and protein kinase C (PKC) signaling, ultimately resulting in the internalization or reverse function of monoamine transporters. Other transporters that methamphetamine is known to inhibit are vesicular monoamine transporter 1 (VMAT1), vesicular monoamine transporter 2 (VMAT2), SLC22A3, and SLC22A5. SLC22A3 is an extraneuronal monoamine transporter that is present in astrocytes and SLC22A5 is a high-affinity carnitine transporter. When methamphetamine interacts with VMAT2, it induces a release of monoamines from the synaptic vesicles (vesicles that stores monoamines) into the cytosol (intracellular fluid) of the presynaptic neuron.

Methamphetamine is also an agonist of the alpha-2 adrenergic receptors and sigma receptors, and inhibits vesicular monoamine transporter 1 (VMAT1), monoamine oxidase B (MAO-B), and monoamine oxidase A (MAO-A). Methamphetamine is known to inhibit the CYP2D6 liver enzyme as well. Dextromethamphetamine is a stronger psychostimulant, but levomethamphetamine has a longer half-life and is CNS-active with weaker effects (approximately one-tenth) on striatal dopamine and shorter perceived effects among addicts. At high doses, both enantiomers of methamphetamine can induce stereotypy and methamphetamine psychosis, but levomethamphetamine is less desired by recreational drug users because of its weaker pharmacodynamic profile.

Although all of the mechanisms are not fully understood, methamphetamine is a known neurotoxin in both lab animals and humans. Beyond neurotoxicity, magnetic resonance imaging studies on human methamphetamine addicts and abusers indicate adverse neuroplastic changes, such as significant abnormalities in various brain structures. In particular, methamphetamine appears to cause white matter hyperintensity and hypertrophy, marked shrinkage of hippocampi, and a reduction in gray matter in the cingulate cortex, limbic cortex, and paralimbic cortex. Moreover, there are adverse changes in various metabolic markers of metabolic integrity or synthesis in methamphetamine abusers, such as reductions in N-acetylaspartate and creatine as well as elevated choline and myoinositol levels.

Comparison to amphetamine pharmacodynamics

Both amphetamine and methamphetamine are potent CNS stimulants with a few biomolecular targets and affected transporters in common; however, there are important pharmacodynamic differences between the two compounds. Both compounds are potent trace amine-associated receptor 1 (TAAR1) agonists (causing non-competitive inhibition of DAT, NET, and SERT) and inhibitors of VMAT2, SLC22A3, and SLC22A5. However, methamphetamine appears to bind at a different site at VMAT2 than amphetamine. Methamphetamine also inhibits VMAT1, has agonist activity at all alpha-2 adrenergic receptor and sigma receptor subtypes, and is directly toxic to dopamine neurons in humans, whereas there is no evidence of acute amphetamine toxicity in humans. Sigma receptor activity is known to potentiate the stimulant and neurotoxic effects of methamphetamine.

In contrast to the adverse neuroplastic effects evident in methamphetamine addicts and abusers, long-term use of amphetamine or methylphenidate at therapeutic doses appears to produce beneficial changes in brain function and structure, such as normalization of the right caudate nucleus.

Pharmacokinetics

Following oral administration, methamphetamine is well-absorbed into the bloodstream, with peak plasma methamphetamine concentrations achieved in approximately 3.13â€"6.3 hours post ingestion. Methamphetamine is also well absorbed following inhalation and following intranasal administration. Due to the high lipophilicity of methamphetamine, it can readily move through the blood brain barrier faster than other stimulants, where it is more resistant to degradation by monoamine oxidase. The amphetamine metabolite peaks at 10â€"24 hours. It is excreted by the kidneys, with the rate of excretion into the urine heavily influenced by urinary pH. When taken orally, 30â€"54% of the dose is excreted in urine as methamphetamine and 10â€"23% as amphetamine. Following IV doses, about 45% is excreted as methamphetamine and 7% as amphetamine. The half-life of methamphetamine is variable with a mean value of between 5â€"12 hours.

CYP2D6, dopamine β-hydroxylase, flavin-containing monooxygenase, butyrate-CoA ligase, and glycine N-acyltransferase are the enzymes known to metabolize methamphetamine or its metabolites in humans. The primary metabolites are amphetamine and 4-hydroxymethamphetamine; other minor metabolites include: 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone, the metabolites of amphetamine. Among these metabolites, the active sympathomimetics are amphetamine, 4â€'hydroxyamphetamine, 4â€'hydroxynorephedrine, 4-hydroxymethamphetamine, and norephedrine.

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination. The known metabolic pathways include:

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. Chiral techniques may be employed to help distinguish the source the drug to determine whether it was obtained illicitly or legally via prescription or prodrug. Chiral separation is needed to assess the possible contribution of levomethamphetamine (e.g., Vicks Vapoinhaler) toward a positive test result. Dietary zinc supplements can mask the presence of methamphetamine and other drugs in urine.

Physical and chemical properties

Methamphetamine is a chiral compound with two enantiomers, dextromethamphetamine and levomethamphetamine. At room temperature, the free base of methamphetamine is a clear and colorless liquid with an odor characteristic of geranium leaves. It is soluble in diethyl ether and ethanol as well as miscible with chloroform. In contrast, the methampetamine hydrochloride salt is odorless with a bitter taste. It has a melting point between 170 to 175 °C (338 to 347 °F) and, at room temperature, occurs as white crystals or a white crystalline powder. The hydrochloride salt is also freely soluble in ethanol and water.

Synthesis

Racemic methamphetamine may be prepared starting from phenylacetone by either the Leuckart or reductive amination methods. 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. In this reaction, an iminium cation is formed as an intermediate which is reduced by the second equivalent of N-methylformamide. The intermediate formyl amide is then hydrolyzed under acidic aqueous conditions to yield methamphetamine as the final product. Alternatively, phenylacetone can be reacted with methylamine under reducing conditions to yield methamphetamine.

Degradation

Bleach exposure time and concentration are correlated with destruction of methamphetamine. Methamphetamine in soils has shown to be a persistent pollutant. Methamphetamine is largely degraded within 30 days in a study of bioreactors under exposure to light in wastewater.

History, society, and culture

Amphetamine, discovered before methamphetamine, was first synthesized in 1887 in Germany by Romanian chemist Lazăr Edeleanu who named it phenylisopropylamine. Shortly after, methamphetamine was synthesized from ephedrine in 1893 by Japanese chemist Nagai Nagayoshi. Three decades later, in 1919, methamphetamine hydrochloride was synthesized by pharmacologist Akira Ogata via reduction of ephedrine using red phosphorus and iodine.

During World War II, Pervitin (methamphetamine) developed by Berlin based Temmler pharmaceutical company was used extensively by all branches of the German armed forces (Luftwaffe pilots, in particular) for its performance enhancing stimulant effects and to induce extended wakefulness. Pervitin became colloquially known among the German troops as "Tank-Chocolates" (Panzerschokolade), "Stuka-Tablets" (Stuka-Tabletten) and "Herman-Göring-Pills" (Hermann-Göring-Pillen).

Obetrol, patented by Obetrol Pharmaceuticals in the 1950s and indicated for treatment of obesity, was one of the first brands of pharmaceutical methamphetamine products. Due to the psychological and stimulant effects of methamphetamine, Obetrol became a popular diet pill in America in the 1950s and 1960s. Eventually, as the addictive properties of the drug became known, governments began to strictly regulate the production and distribution of methamphetamine. For example, during the early 1970s in the United States, methamphetamine became a schedule II controlled substance under the Controlled Substances Act. Currently, methamphetamine is sold under the trade name Desoxyn, trademarked by the Danish pharmaceutical company Lundbeck. As of January 2013, the Desoxyn trademark had been sold to Italian pharmaceutical company Recordati.

Present legal status

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.

See also

• Amphetamine
• Breaking Bad â€" A television series involving the criminal production of methamphetamine
• Faces of Meth
• Levomethamphetamine
• Methamphetamine in the United States
• Montana Meth Project
• Phenelzine
• Rolling meth lab
• Ya ba

Notes

1. ^ Synonyms and alternate spellings include: metamfetamine (International Nonproprietary Name (INN)), N-methylamphetamine, desoxyephedrine, Syndrox, and Desoxyn. Common slang terms for methamphetamine include: speed, meth, crystal, crystal meth, glass, shards, ice, and tic and, in New Zealand, "P".
2. ^ Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.
3. ^ ^{a b} The active ingredient in Vicks Vapoinhaler is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.
4. ^ During short-term treatment, fluoxetine may decrease drug craving.
5. ^ During "medium-term treatment," imipramine may extend the duration of adherence to addiction treatment.
6. ^ They suggest consulting with a Certified Poison Control Center on treatment for up-to-date information, advice, and guidance.

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Reference notes

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References

External links

• Methamphetamine Toxnet entry
• Methamphetamine Poison Information Monograph