++
++
Methamphetamine is known by many names, including, but not limited to, “yaba,” “speed,” “go,” “crack,” “uppers,” and “dexies.” The terms “crystal,” “shard,” and “ice” refer to the crystalline form of methamphetamine. Methamphetamine was first synthesized from ephedrine in Japan in 1893, soon after the synthesis of amphetamine in 1887. Crystallized methamphetamine was synthesized in 1919 through the reduction of ephedrine using red phosphorus. From the 1950s to the 1970s, there were multiple epidemics of methamphetamine abuse in the United States.64 Methamphetamine is approved by the FDA for the short-term treatment of attention-deficit/hyperactivity disorder and obesity, and it is sold under the trade name Desoxyn as a Schedule II drug. It is also prescribed for off-label use for refractory depression and narcolepsy.
++
The production of methamphetamine is relatively simple, requiring minimal equipment and chemicals. There are many methods of methamphetamine production which initially utilize pseudoephedrine, ephedrine, or phenyl-2-propone (P2P). The primary ingredient of methamphetamine synthesis is ephedrine, which can be hydrogenated into methamphetamine. The ephedrine method, using pharmaceutical grade l-ephedrine, produces a product with few contaminants that is stereochemically pure.49,133 P2P, as an alternative ingredient, can be methylated into ephedrine and then transformed into methamphetamine.22 Because of the strict control of ephedrine and P2P, illicit chemists use phenylacetic acid to synthesize P2P.22,42 Lead acetate, which is used as a substrate for the reaction, has resulted in an epidemic of lead poisoning associated with methamphetamine abuse in Oregon.2,121 Mercury contamination was also documented, although clinical mercury toxicity has not been reported.20 Methamphetamine laboratories use many xenobiotics, including phosphine gas, methylamine gas, chloroform, and hydrochloric acid3,81; therefore, these laboratories pose a significant health risk to law enforcement officers and the general public, causing respiratory and ophthalmic irritation, headaches, and burns.28,155 Currently, the sale of other potential amphetamine synthetic ingredients, such as hydrochloric acid, hydrogen chloride gas, anhydrous ammonia, red phosphorus, and iodine, are also monitored and restricted in the United States.22,29
++
Methamphetamine exists as a chiral molecule with two isomers that include levomethamphetamine and dextromethamphetamine. Although the levorotatory form is devoid of CNS stimulatory properties, it retains its vasoactive effects and is used in nonprescription nasal decongestant inhalers. In the racemic mixture, the dextrorotatory form is responsible for the entire stimulant effects observed with methamphetamines. Methamphetamine undergoes metabolism in the liver mainly to amphetamine and 4-hydroxymethamphetamine and has prolonged half-life of 19 to 34 hours, although the duration of its acute effects can be greater than 24 hours.49
+++
3,4-Methylenedioxymethamphetamine (MDMA)
++
++
3,4-Methylenedioxymethamphetamine, also known as MDMA, was first synthesized in 1912, and was rediscovered in 1965 by Shulgin. MDMA is known as “ecstasy,” “E,” “Adam,” “XTC,” “molly,” and “MDM,” and it is commonly abused by college students and teenagers.128,170,174 Other amphetamines that are similar to MDMA, include MDEA (“Eve”) and MDA (“love drug”), which have similar clinical effects, are also used or distributed as MDMA in areas of MDMA use. Amphetamines sold as MDMA include 2CB, 2,4-dimethoxy-4-(n)-propylthiophenylethylamine (2C-T7), and N-methyl-1-(3, 4-methylenedioxyphenyl)-2-butanamine (MBDB).27,63,92 The term “ecstasy” may be used for all these xenobiotics. Typically, MDMA is available in 50 to 200 mg colorful and branded tablets.
++
MDMA and similar analogs are so-called entactogens (meaning touching within), capable of producing euphoria, inner peace, and a desire to socialize.152 In addition, some psychologists used MDMA to enhance psychotherapy until the Controlled Substances Act of 1986 placed MDMA in Schedule I, thereby eliminating its medical use.119 People who use MDMA report that it enhances pleasure, heightens sexuality, and expands consciousness without the loss of control.70 Negative effects reported with acute use included ataxia, restlessness, confusion, poor concentration, and impaired memory.152 MDMA has about one-tenth the CNS stimulant effect of amphetamine. Unlike amphetamine and methamphetamine, MDMA is a potent stimulus for the release of serotonin.24,45,72 The concentration of MDMA required to stimulate the release of serotonin is 10 times less than that required for the release of dopamine or norepinephrine. In animal models, the stereotypic and discriminatory effects of MDMA and its congeners can be distinguished from those of other amphetamines.24
++
The sympathetic effects of MDMA are mild in low doses. However, when a large amount of MDMA is taken, the clinical presentation is similar to that of other amphetamines, and deaths can result from abuse.61,91,138 Those patients at greatest risk develop dysrhythmias, hyperthermia, rhabdomyolysis, and disseminated intravascular coagulation.138 Significant hyponatremia is reported with MDMA use.1,21,75 MDMA and its metabolites increase the release of vasopressin (antidiuretic hormone), and this may be related to the serotonergic effects.56 Furthermore, substantial free water intake combined with sodium loss from physical exertion in dance clubs may exacerbate the development of hyponatremia.
++
Most recently, reports of poisoning from a form of MDMA known as Molly have emerged. Molly is initially thought to be a purified or crystallized form of MDMA that is typically taken orally. Molly use has increased due to what was perceived as a more rapid onset of symptoms and a subtler offset or “come down” period. Molly is also commonly viewed as a safer form of MDMA, since it is believed to contain no adulterants. The use of Molly is associated with adverse effects such as intracranial hemorrhage.85 While Molly is often sold on the street as MDMA, Molly may not be pure MDMA but actually may contain 2C compounds, amphetamines that have two methoxy groups and a halogen such as iodine (2C-I) or bromide (2C-B). The compound 2C-I is known as “smiles.”
++
A major concern with MDMA use is its long-term effects on the brain. In numerous animal models, acute administration of MDMA leads to the decrease in serotonin reuptake transporter (SERT) function and number. Recovery of SERT function may take several weeks. Repetitive administration of MDMA ultimately results in permanent damage to serotonergic neurons, typically causing injury to the axons and the terminals while sparing the cell bodies.112,140,141 Some regeneration of synaptic terminals can occur even with neuronal damage, but functional recovery is incomplete. Intact SERT function is necessary for MDMA-induced neurotoxicity. Xenobiotics that inhibit the reuptake of serotonin prevent MDMA-induced neurotoxicity in animals. Animal data suggest that MDMA induces hydroxyl free-radical generation and decreases antioxidants in serotonergic neurons.149 MDMA itself is not the ultimate neurotoxin, rather its metabolites 3-methyldopamine and N-methyl-α-methyldopamine appear to be responsible in animals.116 When antioxidants are depleted, neuronal damage may occur.
+++
Paramethoxyamphetamine (PMA) and Paramethoxymethamphetamine (PMMA)-Monomethoxy Derivatives
++
++
Para-methoxyamphetamine (PMA) is the 4-methoxylated analog of amphet-amine, and para-methoxy-N-methylamphetamine (PMMA; methyl-MA) is the 4-methoxy analog of methamphetamine. PMA was first produced in 1973 and sold as a hallucinogen for a short period of time, and it reemerged in the 1990s. PMMA soon appeared after PMA, with multiple reports of death also emerging during that time.10,83,97,102 PMA and PMMA are commonly found as tablets or capsules sold as MDMA or “ecstasy.” While the effects of PMA and PMMA mimic some aspect of MDMA and methamphetamine, there are unique properties of PMA and PMMA, that make them considerably more lethal and earning the street name “death.” In recent years, there have been more than 100 fatalities and severe poisonings attributed to PMMA and PMA in the United States, Canada, and Europe.87,100,103,107,109
++
Methoxy ring substitution of amphetamine or methamphetamine at the 3 or 4 positions (para substitution is the most common) yields PMA and PMMA derivatives that have significantly less sympathomimetic activity than amphetamine but very potent serotonergic activity.38,158 Both PMA and PMMA inhibit reuptake of serotonin and inhibit monoamine oxidase A found centrally and peripherally. The methoxy ring substitution is also responsible for poor penetration of the blood brain barrier.6,58
++
PMA and PMMA poisoning lead to autonomic hyperactivity similar to what is observed in other amphetamines such as hypertension, tachycardia, and agitation. The use of PMA and PMMA results in a weak euphoric effect and delayed onset of CNS effects due to poor blood–brain barrier penetration. These properties will often lead users to repeatedly dose themselves that result in serious toxicity and are responsible for the seemingly high mortality rate.
+++
Cathinones (Methcathinone, MDPV, and Mephedrone)—”Bath Salts”
++
++
Cathinone ({S}-2-amino-1-phenyl-1-propanone) is a naturally occurring substance found in the leaves of the Catha edulis (khat) plant. Also known as guat and gat, the fresh leaves and stems are commonly used as a stimulant in Africa and certain Middle Eastern countries such as Yemen. While there are numerous other amphetamines in minute quantities, the primary active ingredient is cathinone. As the leaves age, cathinone is degraded to cathine, which has about one-tenth the stimulant effect of d-amphetamine. Imported fresh khat must be consumed within a week, before it loses much of its potency. The primary effects of khat are increased alertness, insomnia, euphoria, anxiety, and hyperactivity. Khat chewing is linked to cardiac and gastrointestinal disease.125,126
++
The syntheses of cathinone derivatives were reported in the early 1920s, with the production of methcathinone in 1928 and mephedrone in 1929. Methcathinone, the methyl derivative of cathinone, was used in Russia as an antidepressant in the 1930s and 1940s. Also known as “Cat” and “Jeff,” cathinone has been used recreationally, most often in countries formerly part of the Soviet Union, but it also gained popularity in the United States, particularly in Michigan, in the 1990s. Synthetic cathinones have become popular drugs of abuse due to a combination of media attention and widespread Internet availability.134,150 Many other synthetic cathinones have been produced including methylone, mephedrone, butylone, methylenedioxypyrovalerone (MDPV), dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, and MDPV.
++
The synthetic cathinones differ from other amphetamines because they contain a ketone at the β position. For this reason, they are often known as bk-amphetamines. The β-ketone group is responsible for increased polarity, which decreases penetration of the blood–brain barrier. They possess amphetaminelike properties and have sympathomimetic effects, although as a group, they are considered less potent. Some of the synthetics cathinones are reported to cause hyponatremia. Although the mechanism is not clear and may not be similar to MDMA.9,25,26,108,130 Reported complications include compartment syndrome, acute kidney injury, and sudden cardiac death.101,118,139,144,179 An irreversible Parkinson syndrome was also described in chronic users of intravenous methcathinone, particularly in Europe and Russia. The methcathinone was manufactured with the use of potassium permanganate to oxidize ephedrine or pseudoephedrine. In one case series, T1-weighted magnetic resonance imaging showed symmetric hyperintensity in the globus pallidus and in the substantia nigra and innominata in all active methcathinone users, suggestive of manganese poisoning, which was also confirmed with elevated whole blood concentrations.159
++
Synthetic cathinones are often sold as “bath salts” or “plant food” and labeled as “not for human consumption” in an attempt to circumvent controlled substances legislation. The legal status differs among countries and changes over time. In the United States, the synthetic cathinones were initially unscheduled, but they are illegal for human consumption under the Federal Analogue Act of 1986. However, on September 7, 2011, the Drug Enforcement Administration used its emergency scheduling authority to enact temporary control, making possession or sale of methylenedioxypyrovalerone, methylone, and mephedrone illegal until recently, when permanent law has been enacted.
++
++
1-(8-Bromobenzo[1,2-b;4,5-b′]difuran-4-yl)-2-aminopropane, also known as Bromo-dragonFLY (BDF), was first synthesized in 1998. BDF was named after its superficial structural resemblance to a dragonfly, similar to earlier and the less potent dihydrofuran series of compounds nicknamed FLY. BDF is a member of a new class of benzodifurans, which have been used as a potent research tools for investigation of the serotonin receptor family and for a time as potential antidepressants.
++
Structurally, BDF is closely related to other phenylethylamines suchas DOB and 2C-B. BDF contains two furan rings on either side of the benzene ring, creating a fully aromatic tricyclic structure. There are a number of similar compounds to BDF, differing by substitution of the bromide atom with other entities. BDF exists as R- and S-enantiomers, which are both biologically active. The R-enantiomer is considered more potent, with its potent hallucinogenic effect mediated through the 5-HT2A serotonin receptor (also with affinity for the 5-HT2B and 5-HT2C serotonin receptors).127
++
BDF is associated with deaths in Europe and the United States. Reports demonstrate delayed complications from severe peripheral vasoconstriction and limb ischemia that likely result from the potent serotonergic properties of BDF.4,37,166,175
+++
2,5-Dimethoxy-4-Methylamphetamine (DOM) and 2,5-Dimethoxy-4-Iodoamphetamine (DOI)
++
++
2,5-Dimethoxy-4-methylamphetamine (DOM), also known as STP, which stands for “Serenity, Tranquility, and Peace,” emerged in the 1960s as a hallucinogen. It was noted for its delayed onset of action and duration of effect that quickly led to its short-lived appearance. 2,5-Dimethoxy-4-iodoamphetamine (DOI) is another potent hallucinogen, previously sold as a substitute for lysergic acid diethylamide, or LSD.
++
Dimethoxy amphetamine derivatives are structurally characterized by methoxy ring substitution at the 2 and 5 positions on the aromatic ring, with varying additional substitution of hydrophobic moieties at the 4 position. DOM and DOI are both serotonin receptor agonists with selectivity at the 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes. Due to this selectivity, DOM and DOI are often used in scientific research involving study of the 5-HT2 receptor subfamily. DOM exists as a chiral molecule, with the R-(-)-enantiomer considered the more potent.13
++
Potent hallucinogenic effects and dysphoria characterize the use of DOB and DOI, with minimal sympathomimetic effects. These symptoms can often be delayed with a prolonged duration of effect, sometimes refractory to the use of benzodiazepines. There is also report of reversible vasospasm with the use of these dimethoxy amphetamine derivatives.8,19