Introduction to Methamphetamine

Methamphetamine hydrochloride or crystal meth, as it is commonly known, is a long acting, powerful and addictive stimulant closely related to dopamine and the N-methylated analog of amphetamine. Depending on dose and route of administration, the duration goes from longer to longest. It is more toxic in its effects on the central nervous system than amphetamine itself[2], methamphetamine has a high potential to be abused and addiction. Methamphetamine is a colorless as crystals and white as a powder, odorless, bitter-tasting, neutralized with HCl. It easily dissolves in water or alcohol and is taken orally, intra nasally (snorting the powder), by needle injection, or by smoking. Methamphetamine may causes euphoria, increased wakefulness and physical activity and decreased appetite. Chronic, long-term use can lead to psychotic behavior, hallucinations, stroke or heart attack.

Using Methamphetamine

Routes of administration

People generally have a preferred way of administering Methamphetamine, often favoured because of a desired higher bio-availability, and sometimes for the ritual(s) it involves

Smoking - Methamphetamine is smoked, either out of a glass pipe composed of a a bowl and stem, or off foil. This is the most common ROA due to high bio-availability (~90.3%) without the risks of injection, or the discomfort of insufflation or plugging.
Insufflation - Just as snorting most other substances, This produces a quick, but short-lived peak followed by a few hours of coasting. Many users report the effects of insufflation last much longer than smoking. The bio-availability is a surprisingly low ~79%.
Injection - This is a popular ROA among long time users for its quick intense rush and the 100% bio-availability. The risks of injecting street methamphetamine are very high. A regular user is at risk of 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. One also risks putting "cut" into their veins when this is done.
Oral - This ROA is often used for its discreet nature. Users will sometimes empty Tylenol capsules and fill them with Methamphetamine for public use. This is the safest way to ingest methamphetamine, presenting the least amount of risk factors. The only common factor being the substance itself, not taking into consideration each person's individual risk factors. Oral bio-availability of methamphetamine is ~62.7%.
Plugging - This is an uncommon ROA, due to the stigma associated with putting drugs into the rectum (outside medical contexts). Plugging methamphetamine involves inserting the drug into the anus (or vagina) directly, via capsule, or by dissolving it in water and using a hypodermic syringe with the needle removed to squirt the resulting methamphetamine solution into the rectum. Some users report increased sexual satisfaction with this method of administration. Methamphetamine will have a fairly easy onset with a high peak, a long coast and an easy comedown. The bio-availability of suppository methamphetamine use is ~99%

Effects of Methamphetamine

The typical effects of methamphetamine in low doses are improved mood or euphoria, increased alertness, wakefulness and concentration, increased sociability, creative stimulation (for example music, writing, art), decreased appetite, increased libido, feelings of confidence, freedom from care, and interest in even otherwise mundane things and activities. Large doses of methamphetamine have been observed to cause psychosis, rhabdomyolysis, cerebral hemorrhage, life-threatening hyperthermia above 41°C, renal and liver failure, cardiac arrhythmia's, heart attacks, cerebrovascular hemorrhages, strokes and seizures.[3] [4]

As a black market substance methamphetamine is variable in its method of production and quality from one batch to another. Different types of crystal methamphetamine, and quality of crystal methamphetamine can greatly differ depending on country and even city of origin. This variability means the effects of methamphetamine are not going to be uniform. Methamphetamine can also provide different effects as a function of the route of administration used.

Since users of meth often stay awake for long periods of time, the effects experienced during the initial onset can be quite different from the effects experienced during the end of a methamphetamine binge.

Combinations with Methamphetamine

Methamphetamine should not be used with monoamine oxidase inhibitors (MAOIs) or for 14 days following their administration; taking them together may cause serious enough high blood pressure to result in serious organ damage. CYP2D6 inhibitors (e.g., selective serotonin reuptake inhibitors (SSRIs)) prolong the effects of methamphetamine by slowing its metabolism and thereby prolonging its half-life. Methamphetamine may decrease the effects of CNS depressants and increase the effects of stimulants and antidepressants. Methamphetamine may counteract the effects of anti-hypertensives and anti-psychotics. Methamphetamine absorption is pH-dependent, proton pump inhibitors, which reduce gastric acid, interact with methamphetamine to lengthen its half-life.[5]

Different Uses for Methamphetamine

Methamphetamiine (as Desoxyn, methamphetamine hydrochloride tablets) is approved in the USA as an adjunct in treatment of Attention Deficit Disorder with Hyperactivity (a behavioral syndrome characterized by moderate to severe distractibility, short attention span, hyperactivity, impulsivity, and emotional instability, where all are severe enough to be problematic and inappropriate to the developmental stage of the child) in children 6 years or older. Therapeutic doses typically start at 5 mg once or twice a day, these then may be raised in increments of 5 mg until optimal effects are seen; the typical effective dose of methamphetamine for ADHD is 20 to 25 mg daily. [6]

Methamphetamine (in the form of Desoxyn) is also approved in the USA for short-term treatment of obesity that is refractory (has not responded to) other treatments including diets, groups program's or other drugs. This treatment has been shown effective only for a matter of several weeks, methamphetamine's suppression of appetite being quickly subject to tolerance effects. [7]

Pharmacology of Methamphetamine

LD₅₀ (mg/kg) (as the hydrochloride) [8] :
Mice : 70 intraperitoneally

Methamphetamine is a sympathomimetic amine with stimulating effects in both the central and peripheral nervous system including elevation of systolic and diastolic blood pressures and weak bronchodilator and respiratory stimulant action. In humans, orally administered methamphetamine reaches peak blood levels 3-6 hours after ingestion. Methamphetamine is highly lipophilic it crosses the blood brain barrier and will cross the placenta to directly affect fetal tissues and nervous system. Methamphetamine is mainly metabolized in the liver by aromatic hydroxylation, N-dealkylation and deamination and has at least seven metabolites. The elimination half-life of methamphetamine is 10-12 hours. Methamphetamine excretion occurs mostly via urine and is dependent on urine pH, higher pH (alkaline) urine significantly increases methamphetamine half-life by reducing the rate of elimination. Close to two-thirds of an oral dosage is excreted in the urine within the first 24 hours with about two-thirds of that as metabolites and one-third as methamphetamine.[9] [10] [11]

Once in the brain methamphetamine causes a cascading release of norepinephrine, dopamine and serotonin. Methamphetamine increases dopamine and serotonin release from storage vesicles (reverse transport) and blocks their uptake, thereby increasing their cytoplasmic concentrations and making them more readily available for reverse transport. The consequence of an acute dose of methamphetamine increase the neurotransmitters of norepinephrine, dopamine and serotonin.[12] [13] [14]

Chemistry of Methamphetamine

Column 1	Column 2
Systematic(IUPAC) name:	(S) (+)-N-methyl-1-phenylpropan-2-amine
Synonyms:	(αS)-N,α-dimethylbenzeneethanamine, (S)-(+)-N,α-dimethylphenethylamine, d-N-methylamphetamine, d-deoxyephedrine, d-desoxyephedrine, 1-phenyl-2-methylaminopropane, d-phenylisopropylmethylamine, methyl-ß-phenylisopropylamine, Norodin; Amphedroxyn, Desfedrin, Desoxyfed, Desoxyn, Destim, Doxephrin, Drinalfa, Gerobit, Hiropon, Isophen, Madrine, Methamphex, Methedrine, Methylisomyn, Pervitin, Soxysympamine, Syndrox, Tonedron, "speed", "meth", "ice" (hydrochloride)
Molecular Formula:	C10H15N, C10H15N.HCl (hydrochloride)
Molar mass:	149.24 g/mol, 185.70 g/mol (hydrochloride)
CAS Registry Number:	537-46-2, 51-57-0 (hydrochloride)
Melting Point:	170-175℃ (hydrochloride)
Boiling Point:	215.5 °C at 760 mmHg (hydrochloride)
Flash Point:	86.8 °C (hydrochloride)
Solubility:	freely soluble in water, alcohol, chloroform; very slightly soluble in absolute ether
Additionnal data:	none
Notes:	hydrochloride aspect : white crystals; bitter taste

[1]

The name methamphetamine commonly refers to the hydrochloride salt.

The Dangers of Methamphetamine

Physical Health Risks

Neurotoxicity

associated enzymes, their receptors, and their transporters. Methamphetamine has also been shown to produce morphological signs of axonal degeneration, and morphological studies have suggested that the reductions of dopamine and serotonin markers are related to destruction of the axons and axon terminals but not the bodies of the neurons themselves. These neurotoxic effects of methamphetamine appear to be ambient and core body temperature dependent, with higher temperatures associated with greater damage.[15] [16] [17] [18]

Methamphetamine seems to most severely affect dopamine terminals in the striatum, and at most minimally damage dopamine terminals in the nucleus accumbens, olfactory bulb, frontal cortex, and hypothalamus, possibly because of differing densities of dopamine and its transmission in these brain regions. The damage methamphetamine does to serotonin terminals in various brain regions including hippocampus, prefrontal cortex, amygdala, and striatum appears to be of equal severity. [19]

Heart-related problems

There have been reports of increased blood pressure, increased heart rate, stroke and heart attack in adults, and sudden death in patients who have heart problems or heart defects with use of methamphetamine and other stimulants. Continual abuse of methamphetamine can also lead to coronary heart disease and cardiomyopathy.[20] People with heart problems, heart defects, high blood pressure or a family history of these should avoid use of methamphetamine and if prescribed desoxyn ensure their doctor knows of these.[21]

Seizures and other neurological problems

Some reports have indicated that stimulant use can lower seizure thresholds in patients with a history of seizure, patients with EEG abnormalities, but no seizure, and, in rare cases, in patients with neither seizure history nor abnormal EEG. A lowered seizure threshold increases risk of seizure.[22] Amphetamines have been reported to worsen motor and phonic tics in Tourette's syndrome.[23]

Circulation problems in fingers and toes

There have been reports of circulatory problems in the extremities (Peripheral vasculopathy, including Raynaud’s phenomenon) associated with the use of methamphetamine. Symptoms include numbness, cold, pain, and change in colour from pale to blue, to red in fingers and/or toes. Anyone experiencing these symptoms should seek medical attention.[24]

Overdose

Methamphetamine overdoses typically cause restlessness, tremor, severely high blood pressure, hyperreflexia, rapid breathing, confusion, aggression, hallucinations, panic, hyperpyrexia, and rhabdomyolysis. After the stage of excessive central nervous system stimulation, fatigue and depression often occur. Overdose of methamphetamine can cause heart arrhythmias, high or low blood pressure, and circulatory collapse. Methamphetamine overdose also causes nausea, abdominal cramping, vomiting, and diarrhea. In cases of fatal poisoning death is typically preceded by convulsions and coma.[25]

Reported Deaths

Fatalities have been reported associated with methamphetamine use, abuse and overdose. Methamphetamine related deaths often involve cardiovascular complications and these are more likely to occur with injection and smoking of methamphetamine than other routes of administration. In the majority of methamphetamine toxicity related death's other substances are also found to be present, most frequently opiates/opioids or benzodiazepines. Methamphetamine toxicity does not appear to have a clear dosage–response, methamphetamine toxicity related death is associated with both low or high levels of methamphetamine in the blood. Postmortem blood levels of methamphetamine in one study suggest that a fatally toxic dose is >150mg.[26] [27] Reports suggest methamphetamine-related deaths frequently involve multiple congestion, pulmonary oedema, pulmonary congestion, cerebrovascular haemorrhage due to high blood pressure, ventricular fibrillation, acute cardiac failure or hyperpyrexia. Methamphetamine deaths due to septic injection or asphyxia by aspiration of vomit have also been reported. A large proportion of methamphetamine-related fatalities arise from accidents, suicide and homicides, rather than physical causes directly attributable to methamphetamine toxicity. This suggesting toxic methamphetamine doses pose risk of severe psychological and behavioural disturbances.[28]

Sudden deaths, fatal stroke, and hearts attacks have also been reported in adults taking stimulant drugs at usual doses for ADHD.[29]

Mental Health Risks

Psychosis, new or worsened mental illness and suicidal thinking

Reports of new and increased mental illness and symptoms are associated with use of stimulant drugs at regular prescribed doses, including aggressive behaviour and hostility, bipolar depression, mania, psychosis and psychotic symptoms such as hallucinations (particularly auditory) and delusions. One study found that psychotic and manic symptoms in patients without a history of psychosis or mania were rare, happening at a rate of about one in 1000. Methamphetamine use by patients with bipolar disorder may worsen or trigger a manic episode. Use of methamphetamine by patients with a preexisting psychotic disorder can can increase and worsen their behavioural and thought disturbances.[30]

Recreational use of methamphetamine typically involves higher than therapeutic doses and exhibits a pattern of bingeing, and hence is likely to present higher risk of psychotic or manic symptoms even in those with no history. Clinical data show that methamphetamine binges can result in psychosis, but it is not known whether this psychosis is purely the result of the amount ingested in a dose or over the binge, or due to a triggering of pre-existing vulnerability in some methamphetamine users, a combination of these, or the result of methamphetamine related sleep deprivation. Over 25% of those initially diagnosed with methamphetamine induced psychosis after some years developed a primary psychotic disorder, suggesting at least some cases may involve preexisting vulnerability. It has been demonstrated that amphetamines can trigger psychosis in healthy subjects given consecutively higher doses. Though psychosis did not occur in 100% of subjects, it usually occurred after 100–300 mg of amphetamine. But studies indicate only a weak relationship between stimulant psychosis and blood levels of amphetamines.[31]

Methamphetamine should be avoided by those with depression, bipolar illness, psychosis or a history of suicidal thinking or attempts. Any patient prescribed methamphetamine (desoxyn) with a history of depression, bipolar illness, psychosis or a history of suicidal thinking or attempts must ensure their doctor knows of it.

Cognitive impairment

Some studies have found that chronic recreational methamphetamine use is associated with a range of cognitive impairments, including deficits in attention, working memory, and decision-making.[32] [33] [34]
The effects of an acute dose of methamphetamine, however, include improved cognitive functioning in some areas of cognition, for example visuospatial perception, attention, and inhibition.[35]

Side Effects

Common side-effects of methamphetamine use include increased blood pressure, tachycardia, heart palpitations, decreased appetite, tremors or shakes, excessive sweating, headache, insomnia (trouble sleeping), dizziness, stomach upset, increase of motor and phonic tics of Tourette’s syndrome, weight loss, joint and muscle pain, impotence and changes in libido, frequent or prolonged erections, and dry mouth.[36]

Chronic abuse of methamphetamine can lead to anxiety, depression, aggressiveness, social isolation, psychosis, mood disturbances, and psychomotor dysfunction [37] [38]

Suppression of growth has been shown to be a side-effect of long-term use of stimulants in children, specifically methylphenidate. Though not established by data (yet) common sense urges caution and an expectation that this could also be a side-effect of long-term methamphetamine (desoxyn) use in children.

Addiction

Physical Addiction

Methamphetamine use for extended periods leads to tolerance and dependence. Stopping such chronic methamphetamine use, especially abruptly and/or after long term use at high doses can cause extreme fatigue or tiredness, depression, disruptions of sleep.[39]

Mental Addiction

Prolonged methamphetamine use leads to tolerance and extreme psychological dependence. Withdrawal from methamphetamine can produce anhedonia (loss of any feelings of pleasure), irritability, fatigue, impaired social functioning, and intense craving for methamphetamine. [40] [41]

Producing Methamphetamine

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.

Forms of Methamphetamine

Methamphetamine is generally found as one of its two enantiomers : S, or as a 50:50 mix of S-methamphetamine and R-methamphetamine, also called a racemic mixture. The stereocenter is the methyl-bearing carbon connected to the methylamine.

The optical isomers (enantiomers) of methamphetamine refract a polarized light ray at the same absolute specific rotation, a standard measure of th degree of the angle of refraction of the ray, but of opposed sign. Systematically, we attribute the suffix dextrorotatory (d) if the ray is diffracted at the right of the observer and levorotatory (l) when on the left. In the case of amphetamines, amino acid nomenclature is more commonly used, as they are analogs of the amino acid : S-methamphetamine = d-methamphetamine and R-methamphetamine = l-methamphetamine.

Enantiomers have the same properties in an achiral environment (i.e. if you used it as an alkylamine base in an achiral chemical reaction). In a chiral environment, such as our body and enzymes, properties of both enantiomers differ. All amphetamines (MDMA, cathinones, MDA, DOB, etc) are chiral molecules. The enantiomeric excess depends completely on the starting material and synthetic approach.

Ephedrine and its diastereomer pseudo-ephedrine were used as a precursor to produce d-methamphetamine, whereas methamphetamine produced with P2P (phenylacetone) provides a racemic mixture, d and l-methamphetamine in equal proportions. The (pseudo-)ephedrine reaction already has the right stereochemistry on the side-chain methyl. Reduction of the alcool does not cause epimerization on the other stereocenter, providing only d-methamphetamine. Old timers in the meth scene will attest to the desire of using d-meth over the more commonly found dl-methamphetamine (racemic mixture).

The way the different isomers of meth effect the body is relative to the way they bind to the receptors on the brain as d-meth will bind more efficiently than the l-meth. When the remnants of l-meth does not bind as nicely as d-meth, it is metabolized faster than the d-meth (which is still hard at work pleasuring the user) and is broken down faster to hydroxyl substituted compounds and excreted out of the body faster.

Methamphetamine can be found in different physical consistencies. These are relative to the way the chemist (or cook in most cases) goes about forming the crystal during the last stage of the production process. Methamphetamine that is powdery in consistency is likely produced when the freebase oil of meth is gassed into the hydrochloride salt of the compound. Methamphetamine that is produced by acid titration will yield a more solid crystal of the compound. If however, the methamphetamine that is gassed out of solution from the freebase oil is recrystallized using a solvent (generally methanol) the result is a dense crystal rock, similar to that of rock candy.

Methamphetamine that has a color to it, is not considered "pure" meth, as an impurity has resulted. A prime example is the blue meth depicted in AMC's hit T.V show Breaking Bad. In this example, a food coloring agent has been added during the final stage of crystallization. In this scenario, the purity is decreased so little, it could still be considered "pure" meth, as it's negligible due to the small amount used.

Other colors, such as pink or slight green could also be a coloring agent, but likely un-reacted precursor or intermediate used in the manufacturing process.

Legal status of Methamphetamine

United Nations

Methamphetamine is in schedule II of the United Nations Convention on Psychotropic Substances treaty.

USA

In the United States, methamphetamine is a schedule II stimulant. This means that, within the U.S., methamphetamine has recognized medical uses but it is illegal to sell without a DEA license and illegal to buy or possess without a license or prescription.

EU

In the UK methamphetamine is a Class A drug under the Misuse of Drugs Act 1971. The maximum penalty for unlawful possession of methamphetamine is 7 years in prison; for supplying or offering to supply methamphetamine or unlawful possession of methamphetamine with intent to supply the maximum penalty is life in prison; and for allowing premises you occupy or manage to be used unlawfully for the purpose of producing or supplying methamphetamine the maximum penalty is 14 years.

Canada

In Canada, methamphetamine has no recognized medical uses and is a Schedule I controlled substance, meaning that the maximum available sentences for distribution or production of methamphetamine is life in prison.

Australia

In Australia, methamphetamine is a schedule 8 controlled. This means that methamphetamine has recognized medical uses. Methamphetamine is never medically prescribed as there are no licensed manufacturers of methamphetamine in Australia.

History of Methamphetamine

We begin with the discovery in China of a stimulant that was in a rare herb called Ma huang. This stimulant was used in Chinese medicine for over 5000 years. It’s not until the late 1800 that scientists are able to isolate the source of the stimulation. Nagayoshi Nagai was able to isolate ephedrine as the source of the stimulant properties of the Ma huang. 2 years later in 1887 Lazar Edelano is able to synthesis an ephedrine like amphetamine called phenyisopropylamine. This and other findings and experiments lead to the creation of methamphetamine in 1893 by none other than the one able to isolate the ephedrine to begin with, chemist Nagayoshi Nagai. It’s not until 26 years later that Akira Ogata was able to create crystallized methamphetamine.

American Gordon Alles of UCLA is able to reproduce Edelano’s results and synthesise phenyisopropylamine in America. This patent is then sold to Smith, Kline and French and marketed as Benzedrine. The public is able to freely abuse Benzedrine throughout the great depression and WWII. Benzedrine is reformulated into tablet form as a treatment for narcolepsy in 1937 and one year later methamphetamine is released to the German public as Pervitin. Most countries involved in WWII on both sides experimented and gave methamphetamine to soldiers to increase alertness for long missions and battles. This was taking place in the late 1930s and quietly at present day methamphetamine and amphetamines are used by most militaries throughout the world.

The first meth epidemic takes place in Japan between 1945-50 it spreads to Guam and the US Marshal islands. Later on in the 1950s and 1960s meth is marketed throughout the world as “pep pills” and sold for non-medical reasons. In the 1950s methamphetamine was used by Korean doctors to treat soldiers morphine addiction not to mention during the 1960s that San Francisco drug clinics prescribed injections of methamphetamine to treat heroin abuse.

It wasn’t until 1970 that the US Congress decided to regulate methamphetamine and other drugs through passage of the Controlled Substances Act (essentially the beginning of the drug war) this had an effect of forcing use and creation of the drug underground. It was during the 1980s that new syntheses were discovered and smoke-able forms of the drug were introduced to the world. This went on into the 1990s when The US Congress again moved on methamphetamine when in 1996 the comprehensive methamphetamine control act was passed regulating mail orders and the precursors necessary to produce methamphetamine.

As of 2000 to present The US and the world have chosen methamphetamine as the hard drug of choice, surpassing Crack Cocaine and Heroin.[42]

References

1. ^Mendelson, John E et al. “The clinical pharmacology of intranasal l-methamphetamine.” BMC clinical pharmacology, 2008, 8 (4)
2. ^Yu, S., Zhu, L., Shen, Q., Bai, X., & Di, X. Recent Advances in Methamphetamine Neurotoxicity Mechanisms and Its Molecular Pathophysiology. Behavioural Neurology, 2015[/b], pp. 1–11.
3. ^Cruikskank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine Addiction 2009 Jul;104(7):1085-99.
4. ^Schepers RJ, Oyler JM, Joseph RE Jr, Cone EJ, Moolchan ET, Huestis MA. Methamphetamine and amphetamine pharmacokinetics in oral fluid and plasma after controlled oral methamphetamine administration to human volunteers. Clin. Chem 2003;49:121–132. [PubMed: 12507968]
5. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
6. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
7. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
8. ^Merck Index, fifteenth edition (2013)
9. ^Cruikskank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine Addiction 2009 Jul;104(7):1085-99.
10. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
11. ^Schepers RJ, Oyler JM, Joseph RE Jr, Cone EJ, Moolchan ET, Huestis MA. Methamphetamine and amphetamine pharmacokinetics in oral fluid and plasma after controlled oral methamphetamine administration to human volunteers. Clin. Chem 2003;49:121–132. [PubMed: 12507968]
12. ^Cruikskank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine Addiction 2009 Jul;104(7):1085-99.
13. ^ (Yamamoto BK, Moszczynska A, Gudelsky GA. Amphetamine toxicities: classical and emerging mechanisms (2010) Ann N Y Acad Sci. 2010 Feb;1187:101-21.)
14. ^Sulzer D. (2011) How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69, 628 649.
15. ^Cruikskank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine Addiction 2009 Jul;104(7):1085-99.
16. ^U.D. McCann, G.A. Ricaurte. Amphetamine neurotoxicity: accomplishments and remaining challenges. Neuroscience and Biobehavioral Reviews 27 (2004) 821–826.)
17. ^Xie T, McCann UD, Kim S, Yuan J, Ricaurte GA. Effect of temperature on dopamine transporter function and intracellular accumulation of methamphetamine: implications for methamphetamine-induced dopaminergic neurotoxicity. J. Neurosci 2000;20:7838–7845. [PubMed: 11027249]
18. ^Irina N. Krasnova and Jean Lud Cadet Methamphetamine Toxicity and Messengers of Death. Brain Res Rev. 2009 May ; 60(2): 379–407. doi:10.1016
19. ^Yamamoto BK, Moszczynska A, Gudelsky GA.Amphetamine toxicities: classical and emerging mechanisms. Ann N Y Acad Sci. 2010 Feb;1187:101-21.)
20. ^Cruikskank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine Addiction 2009 Jul;104(7):1085-99.
21. ^Sulzer D. (2011) How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69, 628 649.
22. ^Cruikskank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine Addiction 2009 Jul;104(7):1085-99.
23. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
24. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
25. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
26. ^Sharlene Kaye, Shane Darke, Johan Duflou & Rebecca McKetin. Methamphetamine-related fatalities in Australia: demographics, circumstances, toxicology and major organ pathology. Addiction. 2008 Aug;103(8):1353-60. doi: 10.1111/j.1360-0443.2008.02231.x.
27. ^Robert S. Gable. Comparison of acute lethal toxicity of commonly abused psychoactive substances. Addiction, 2004. 99, 686–696.
28. ^Cruikskank CC, Dyer KR. A review of the clinical pharmacology of methamphetamine Addiction 2009 Jul;104(7):1085-99.
29. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
30. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
31. ^Bramness et al. Amphetamine-induced psychosis - a separate diagnostic entity or primary psychosis triggered in the vulnerable? BMC Psychiatry 2012, 12:221
32. ^Gonzalez R, Rippeth JD, Carey CL, Heaton RK, Moore DJ, Schweinsburg BC, Cherner M, Grant I. Neurocognitive performance of methamphetamine users discordant for history of marijuana exposure. Drug Alcohol Depend 2004;76:181–190. [PubMed: 15488342]
33. ^Semple SJ, Zians J, Grant I, Patterson TL. Impulsivity and methamphetamine use. J. Subst. Abuse Treat 2005;29:85–93. [PubMed: 16135337]
34. ^Paulus MP, Hozack NE, Zauscher BE, Frank L, Brown GG, Braff DL, Schuckit MA. Behavioral and
    functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects. Neuropsychopharmacology 2002;26:53–63. [PubMed: 11751032]
35. ^Carl L Hart, Caroline B Marvin, Rae Silver and Edward E Smith. Is Cognitive Functioning Impaired in Methamphetamine Users? A Critical Review. Neuropsychopharmacology (2012) 37, 586–608; doi:10.1038/npp.2011.276; published online 16 November 2011
36. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
37. ^Darke S, Kaye S, McKetin R, Duflou J. Major physical and psychological harms of methamphetamine use. Drug Alcohol Rev 2008;27:253–262. [PubMed: 18368606]
38. ^Zweben JE, Cohen JB, Christian D, Galloway GP, Salinardi M, Parent D, Iguchi M. Psychiatric symptoms in methamphetamine users. Am. J. Addict 2004;13:181–190. [PubMed: 15204668]
39. ^Desoxyn (methamphetamine hydrochloride tablets USP) monograph (revised 2013) Recordati Rare Diseases.
40. ^Homer BD, Solomon TM, Moeller RW, Mascia A, DeRaleau L, Halkitis PN. Methamphetamine abuse and impairment of social functioning: a review of the underlying neurophysiological causes and behavioral implications. Psychol. Bull 2008;134:301–310. [PubMed: 18298273]
41. ^Zweben JE, Cohen JB, Christian D, Galloway GP, Salinardi M, Parent D, Iguchi M. Psychiatric symptoms in methamphetamine users. Am. J. Addict 2004;13:181–190. [PubMed: 15204668]
42. ^reference needed