Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants, as well as enhancing the reward memory of pollinators. It is most commonly consumed by humans in infusions extracted from the seed of the coffee plant and the leaves of the tea bush, as well as from various foods and drinks containing products derived from the kola nut. Other sources include yerba maté, guarana berries, guayusa, and the yaupon holly.

In humans, caffeine acts as a central nervous system stimulant, temporarily warding off drowsiness and restoring alertness. It is the world's most widely consumed psychoactive drug, but unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of the world. Beverages containing caffeine, such as coffee, tea, soft drinks, and energy drinks, enjoy great popularity. In North America, 90%% of adults consume caffeine daily.

Part of the reason caffeine is classified by the Food and Drug Administration as GRAS (generally recognized as safe) is that toxic doses (over 10 grams) are much higher than typically used doses (less than 500 milligrams). Ordinary consumption can have low health risks, even when carried on for years – there may be a modest protective effect against some diseases, including Parkinsons Disease, and certain types of cancer. Caffeine can have both positive and negative effects on anxiety disorders. Some people experience sleep disruption if they consume caffeine, especially during the evening hours, but others show little disturbance and the effect of caffeine on sleep is highly variable.

Evidence of a risk to pregnancy is equivocal, but some authorities have concluded that prudent advice is for pregnant women to limit consumption to the equivalent of two cups of coffee per day or less. The American Congress of Obstetricians and Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per day in pregnant women. Caffeine has pressor and mild diuretic effects when administered to people who are not used to it, but regular users develop a tolerance to this effect, and studies have generally failed to support the common notion that ordinary consumption contributes significantly to dehydration. With heavy use, tolerance develops rapidly to autonomic effects such as elevated heart rate and muscle twitching, but not to the cognitive or arousal effects of caffeine. The degree to which caffeine can produce clinically significant physical and mental dependence remains a subject of controversy in the medical literature.


Health effects

Stimulant effects

Caffeine is a central nervous system and metabolic stimulant, and is used both recreationally and medically to reduce physical fatigue and to restore alertness when drowsiness occurs. It produces increased wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination. The amount of caffeine needed to produce effects varies from person to person, depending on body size and degree of tolerance. Effects begin less than an hour after consumption, and a moderate dose usually wears off in about five hours.

Caffeine has a number of effects on sleep, but does not affect all people in the same way. It improves performance during sleep deprivation but may lead to subsequent insomnia. In shift workers it leads to fewer mistakes caused by tiredness. In athletics, moderate doses of caffeine can improve sprint, endurance, and team sports performance, but the improvements are usually not very large. Interestingly, some evidence suggests that coffee does not produce the ergogenic effects observed in other caffeine sources. High doses of caffeine, however, can impair athletic performance by interfering with coordination. Evidence shows that, contrary to common advice, caffeine may be helpful at high altitude.


Physical effects

Consumption of large amounts of caffeine – usually more than 250 mg per day – can lead to a condition known as caffeinism. Caffeinism usually combines caffeine dependency with a wide range of unpleasant physical and mental conditions including nervousness, irritability, restlessness, insomnia, headaches, and heart palpitations after caffeine use.

Coffee consumption is associated with a lower overall risk of cancer. This is primarily due to a decrease in the risks of hepatocellular and endometrial cancer, but it may also have a modest effect on colorectal cancer. There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk of bladder cancer. On the other hand, caffeine has been shown to inhibit cellular DNA repair mechanisms., but only at extreme high concentrations (which would be lethal in humans). There is little or no evidence that caffeine consumption increases the risk of cardiovascular disease, and it may somewhat reduce the risk of type 2 diabetes. Drinking four or more cups of coffee per day does not affect the risk of hypertension compared to drinking little or no coffee. However those who drink 1–3 cups per day may be at a slightly increased risk. Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals. It may protect people from liver cirrhosis. There is no evidence that coffee stunts a child's growth. Caffeine may increase the effectiveness of some medications including ones used to treat headaches. Similarly, intravenous caffeine is often used in hospitals to provide temporary pain relief for headaches associated caused by low cerebrospinal fluid pressure.

Caffeine consumption during pregnancy does not appear to increase the risk of congenital malformations, miscarriage or growth retardation even when consumed in moderate to high amounts. However as the data supporting this conclusion is of poor quality some suggest limiting caffeine consumption during pregnancy. For example the UK Food Standards Agency has recommended that pregnant women should limit their caffeine intake, out of prudence, to less than 200 mg of caffeine a day – the equivalent of two cups of instant coffee, or one and a half to two cups of fresh coffee. The American Congress of Obstetricians and Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per day in pregnant women. Although the evidence that caffeine may be harmful during pregnancy is equivocal, there is some evidence that the hormonal changes associated with pregnancy slow the metabolic clearance of caffeine from the system, causing a given dose to have longer-lasting effects (as long as 15 hours in the third trimester).

On the positive side, caffeine is the primary treatment of the breathing disorders apnea of prematurity and may also be effective in preventing bronchopulmonary dysplasia in premature infants. The only short-term risk associated with caffeine citrate treatment is a temporary reduction in weight gain during the therapy, and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine. While some authors have raised the possibility of subtle long-term problems, follow-up neurological data at 18 months and at five years after neonatal caffeine treatment revealed the opposite; treatment appears to be neuroprotective, as caffeine-treated children were significantly less likely to have cerebral palsy and had reduced rates of language and cognitive delay.

When doses of caffeine equivalent to 2–3 cups of coffee are administered to people who have not consumed caffeine during prior days, they produce a mild increase in urinary output. Because of this diuretic effect, some authorities have recommended that athletes or airline passengers avoid caffeine in order to reduce the risk of dehydration. Most people who consume caffeine, however, ingest it daily. Regular users of caffeine have been shown to develop a strong tolerance to the diuretic effect, and studies have generally failed to support the notion that ordinary consumption of caffeinated beverages contributes significantly to dehydration, even in athletes.

Caffeine has been demonstrated to increase muscle performance: Coso et al. found that a caffeine dose of at least 3 mg/kg in the form of an energy drink improved half-squat and bench-press maximal muscle power.


Psychological effects

The US National Institutes of Health states:

Too much caffeine can make you restless, anxious, and irritable. It may also keep you from sleeping well and cause headaches, abnormal heart rhythms, or other problems. If you stop using caffeine, you could get withdrawal symptoms. Some people are more sensitive to the effects of caffeine than others. They should limit their use of caffeine. So should pregnant and nursing women.


Four caffeine-induced disorders are recognized by the American Psychiatric Association (APA) including: caffeine intoxication, caffeine-induced sleep disorder, caffeine-induced anxiety disorder and caffeine-related disorder not otherwise specified (NOS). The DSM-IV defines caffeine-induced sleep disorder, as an individual who regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention. As of 2010 the effect of caffeine on people with ADHD is not known. Some studies have however found a modest protective against Alzheimer disease, but the evidence is inconclusive.

Caffeine can have both negative and positive effects on anxiety disorders. A number of clinical studies have shown a positive association between caffeine and anxiogenic effects and/or panic disorder. At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety or, rarely, trigger mania or psychosis. In moderate doses caffeine may reduce symptoms of depression and lower suicide risk. In moderate doses caffeine typically does not affect learning or memory, and can improve cognitive functions, especially in people who are fatigued, possibly due to its effect on alertness. However anxiety sufferers can have high caffeine sensitivity. For some people, anxiety can be very much reduced by discontinuing caffeine use.

Contrary to popular belief, some research suggests that caffeine does not increase motivation in humans, and may even decrease motivation in some.


Caffeine toxicity

Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90),. This syndrome typically occurs only after ingestion of large amounts of caffeine, well over the amounts found in typical caffeinated beverages and caffeine tablets (e.g. more than 400–500 mg per at a time). The symptoms of caffeine intoxication are comparable to the symptoms of overdoses of other stimulants: they may include restlessness, fidgeting, anxiety, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation. In cases of much larger overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations, or psychosis may occur, and rhabdomyolysis (breakdown of skeletal muscle tissue) can be provoked.

Extreme overdose can result in death. The median lethal dose (LD50) given orally, is 192 milligrams per kilogram in rats. The LD50 of caffeine in humans is dependent on individual sensitivity, but is estimated to be about 150 to 200 milligrams per kilogram of body mass or roughly 80 to 100 cups of coffee for an average adult. Though achieving lethal dose with caffeine would be difficult with regular coffee, there have been reported deaths from overdosing on caffeine pills, with serious symptoms of overdose requiring hospitalization occurring from as little as 2 grams of caffeine. An exception to this would be taking a drug such as fluvoxamine or levofloxacin, which blocks the liver enzyme responsible for the metabolism of caffeine, thus increasing the central effects and blood concentrations of caffeine five-fold. The exact cause of death in such cases is uncertain, but may result from cardiac arrythmia leading to cardiac arrest.

Treatment of severe caffeine intoxication is generally supportive, providing treatment of the immediate symptoms, but if the patient has very high serum levels of caffeine then peritoneal dialysis, hemodialysis, or hemofiltration may be required.


Addiction and tolerance

With repetitive use, physical dependence or addiction may occur. Also, some effects of caffeine, particularly the autonomic effects, decrease over time, a phenomenon known as a tolerance. Tolerance develops quickly to some (but not all) effects of caffeine, especially among heavy coffee and energy drink consumers. Some coffee drinkers develop tolerance to its sleep-disrupting effects, but others apparently do not.


Withdrawal

Withdrawal symptoms – including headache, irritability, inability to concentrate, drowsiness, insomnia, and pain in the stomach, upper body, and joints – may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from 2 to 9 days. Withdrawal headaches are experienced by 52%% of people who stopped consuming caffeine for two days after an average of 235 mg caffeine per day prior to that. In prolonged caffeine drinkers, symptoms such as increased depression and anxiety, nausea, vomiting, physical pains and intense desire for caffeine containing beverages are also reported. Peer knowledge, support and interaction may aid withdrawal.


Other animals

While safe in humans, caffeine is considerably toxic to various animals, such as dogs and birds. The increased toxicity of caffeine in some animals is at least partly due to a poorer ability to metabolize the compound. Caffeine also has a pronounced effect on mollusks, various insects, and spiders.


Sources and consumption

Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance. This amounts to one serving of a caffeinated beverage for every person every day.

Caffeine is found in many plant species, where it acts as a natural pesticide, with high caffeine levels being observed in seedlings still developing foliage but lacking mechanical protection; caffeine paralyzes and kills certain insects feeding on the plant. High caffeine levels have also been found in the surrounding soil of coffee bean seedlings. Therefore, caffeine is understood to have a natural function as both a natural pesticide and an inhibitor of seed germination of other nearby coffee seedlings, thus giving it a better chance of survival. Caffeine has also been found to enhance the reward memory of honeybees, improving the reproductive success of the plant.

Common sources of caffeine are coffee, tea, soft drinks and energy drinks, and (to a lesser extent) chocolate derived from cocoa beans. Less commonly used sources of caffeine include the yerba maté, guarana and ilex guayusa plants, which are sometimes used in the preparation of teas and energy drinks. Two of caffeine's alternative names, mateine and guaranine, are derived from the names of these plants.

The disparity in experience and effects between the various natural caffeine sources could be because plant sources of caffeine also contain widely varying mixtures of other xanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and other substances such as polyphenols that can form insoluble complexes with caffeine.

One of the world's primary sources of caffeine is the coffee bean (which is the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method of preparation used; even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 80–100 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to approximately 100–125 milligrams for a cup (120 milliliters) of drip coffee. Arabica coffee typically contains half the caffeine of the robusta variety.

In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the roasting process reduces a small amount of the bean's caffeine content.

Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since tea is normally brewed much weaker. Also contributing to caffeine content are growing conditions, processing techniques, and other variables. Thus, certain types of tea may contain somewhat more caffeine than other teas.

Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee. Preparation and many other factors have a significant impact on tea, and color is a very poor indicator of caffeine content. Teas like the pale Japanese green tea, gyokuro, for example, contain far more caffeine than much darker teas like lapsang souchong, which has very little.

Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 to 50 milligrams of caffeine per serving. By contrast, energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.

Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine. A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee, although dark chocolate has about the same caffeine as coffee by weight. And some dark chocolate currently in production contain as much as 160 mg per 100 g -which is double the caffeine content of the highest caffeinated drip coffee by weight.

Various manufacturers market caffeine tablets, claiming that using caffeine of pharmaceutical quality improves mental alertness. These effects have been borne out by research that shows caffeine use (whether in tablet form or not) results in decreased fatigue and increased attentiveness.

These tablets are commonly used by students studying for their exams and by people who work or drive for long hours. One U.S. company is also marketing dissolving caffeine strips as an alternative to energy drinks. Another unusual intake route is SpazzStick, a caffeinated lip balm. As of 2013, a number of innovative caffeinated products such as Alert Energy Caffeine Gum, a Wrigley product, had been introduced in the United States, but were under scrutiny; after announcement of an investigation by the FDA of the health effects of added caffeine in foods, Alert Energy Caffeine Gum was voluntarily withdrawn from sale.


Chemical properties and biosynthesis

Caffeine is an achiral molecule without stereoisomers.

The two amide groups of caffeine exist predominately as zwitterionic resonance structures where the nitrogen and carbon atoms are double bonded to each other so that both of these nitrogen atoms are essentially planar (in sp2 orbital hybridization). The fused ring system therefore contains a total of ten pi electrons and hence according to Hückel's rule is aromatic.

Caffeine is synthesized in plants from the purine nucleotides AMP, GMP, and IMP. These in turn are transformed into xanthosine and then theobromine, the latter being the penultimate precursor of caffeine.

Being readily available as a byproduct of decaffeination, caffeine is not usually synthesized chemically. If desired, it may be synthesized from dimethylurea and malonic acid.

Pure anhydrous caffeine is a white colorless powder with a melting point of 227–228 °C. Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL). It is also moderately soluble in ethanol (1.5 g/100 mL). It is weakly basic (pKa = ~0.6) requiring strong acid to protonate it.


Pharmacology

Inside the body caffeine acts through several mechanisms, but its most important effect is to counteract a substance called adenosine that naturally circulates at high levels throughout the body, and especially in the nervous system. In the brain, adenosine plays a generally protective role, part of which is to reduce neural activity levels – for example, there is some evidence that adenosine helps to induce torpor in animals that seasonally hibernate.


Mechanism of action

Adenosine acts as an inhibitor neurotransmitter that suppresses activity in the central nervous system. Consumption of caffeine antagonizes adenosine and increases activity in neurotransmission including acetylcholine, epinephrine, dopamine, serotonin, glutamate, norepinephrine, cortisol, and in higher doses, endorphins which explains the analgesic effect to some users. At very high doses (exceeding 500 milligrams) caffeine inhibits GABA neurotransmission. This evidence explains why caffeine causes anxiety, insomnia, rapid heart and respiration rate.

Because caffeine is both water-soluble and lipid-soluble, it readily crosses the blood–brain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors (in other words, an agent that reduces the effects of adenosine). The caffeine molecule is structurally similar to adenosine, and is capable of binding to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive inhibitor.

Adenosine is found in every part of the body, because it plays a role in the fundamental adenosine triphosphate (ATP) related energy producing mechanism and is also needed for RNA synthesis, but it has additional functions in the brain. The evidence indicates that brain adenosine acts to protect the brain by suppressing neural activity and by increasing blood flow via receptors located on vascular smooth muscle. Brain adenosine levels are increased by various types of metabolic stress, including lack of oxygen and interruption of blood flow. There is evidence that adenosine functions as a synaptically released neurotransmitter in some parts of the brain; however, stress-related adenosine increases appear to be produced mainly by extracellular metabolism of ATP. Unlike most neurotransmitters, adenosine does not seem to be packaged into vesicles that are released in a voltage-controlled manner, but the possibility of such a mechanism has not been ruled out fully.

Several classes of adenosine receptors have been described, with different anatomical distributions. A1 receptors are widely distributed, and act to inhibit calcium uptake. A2A receptors are heavily concentrated in the basal ganglia, an area that plays a critical role in behavior control, but can be found in other parts of the brain as well, in lower densities. There is evidence that A 2A receptors interact with the dopamine system, which is involved in reward and arousal. (A2A receptors can also be found on arterial walls and blood cell membranes.)

Beyond its general neuroprotective effects, there are reasons to believe that adenosine may be more specifically involved in control of the sleep-wake cycle. Robert McCarley and his colleagues have argued that accumulation of adenosine may be a primary cause of the sensation of sleepiness that follows prolonged mental activity, and that the effects may be mediated both by inhibition of wake-promoting neurons via A1 receptors, and activation of sleep-promoting neurons via indirect effects on A2A receptors. More recent studies have provided additional evidence for the importance of A2A, but not A1, receptors.

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor. A number of potential mechanisms have been proposed for the athletic performance-enhancing effects of caffeine. In the classic, or metabolic theory, caffeine may increase fat utilization and decrease glycogen utilization. Caffeine mobilizes free fatty acids from fat and/or intramuscular triglycerides by increasing circulating epinephrine levels. The increased availability of free fatty acids increases fat oxidation and spares muscle glycogen, thereby enhancing endurance performance. In the nervous system, caffeine may reduce the perception of effort by lowering the neuron activation threshold, making it easier to recruit the muscles for exercise.


Caffeine metabolites

Metabolites of caffeine also contribute to caffeine's effects. Paraxanthine is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and force of contraction.


Metabolism

Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and then distributed throughout all tissues of the body. Peak blood concentration is reached within one hour. It is eliminated by first-order kinetics. Caffeine can also be absorbed rectally, evidenced by the formulation of suppositories of ergotamine tartrate and caffeine (for the relief of migraine) and chlorobutanol and caffeine (for the treatment of hyperemesis).

The biological half-life of caffeine – the time required for the body to eliminate one-half of the total amount of caffeine – varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. It can also be significantly altered by drugs or hormonal states. In healthy adults, caffeine's half-life has been measured with a range of results. Some measures get 4.9 hours, and others are at around 6 hours. Heavy cigarette smokers show a decrease in half-life of 30–50%%, oral contraceptives can double it, and pregnancy can raise it even more, to as much as 15 hours during the last trimester. In newborn infants the half-life can be 80 hours or more; however it drops very rapidly with age, possibly to less than the adult value by the age of 6 months. The antidepressant fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%%, and prolongs its elimination half-life more than tenfold; from 4.9 hours to 56 hours.

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines, each of which has its own effects on the body:


Paraxanthine (84%%): Increases lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.

Theobromine (12%%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean, and therefore chocolate.

Theophylline (4%%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.


Each of these metabolites is further metabolized and then excreted in the urine. Caffeine can accumulate in individuals with severe liver disease, increasing its half-life.

Some quinolone antibiotics exert an inhibitory effect on CYP1A2, thereby reducing clearance of caffeine and thus increasing blood levels.

A 2011 analysis published by PLoS Genetics reviewed five studies covering more than 47,000 subjects of European descent. Researchers determined that habitual caffeine intake is associated with variations in two genes that regulate how quickly the body processes caffeine. Subjects who had a high-intake mutation of either gene on both chromosomes consumed 40 mg more caffeine per day (equivalent to a can of cola) than people who did not.


Detection in biological fluids

Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a diagnosis of poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are usually in the range of 2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates receiving treatment for apnea, and 40–400 mg/L in victims of acute overdosage. Urinary caffeine concentration is frequently measured in competitive sports programs, for which a level in excess of 15 mg/L is usually considered to represent abuse.


Decaffeination

Extraction of caffeine from coffee, to produce decaffeinated coffee and caffeine, is an important industrial process and can be performed using a number of different solvents. Benzene, chloroform, trichloroethylene, and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost, and flavor, they have been superseded by the following main methods:


Water extraction: Coffee beans are soaked in water. The water, which contains many other compounds in addition to caffeine and contributes to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with its original flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets.

Supercritical carbon dioxide extraction: Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a supercritical state: It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99%% of the caffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.

Extraction by organic solvents: Certain organic solvents such as ethyl acetate present much less health and environmental hazard than chlorinated and aromatic organic solvents used formerly. Another method is to use triglyceride oils obtained from spent coffee grounds.


'Decaffeinated' coffees do in fact contain caffeine, although only about 10 mg per cup as opposed to 85 mg per cup from regular.


History

Caffeine was first isolated from coffee in 1820 by the German chemist Friedlieb Ferdinand Runge, and then independently in 1821 by French chemists Pierre Robiquet, Pierre Pelletier, and Joseph Caventou. Pelletier coined the word cafeine from the French word for coffee (café), and this term became the English word caffeine.

According to Chinese legend, the Chinese emperor Shennong, reputed to have reigned in about 3000 BCE, accidentally discovered tea when he noted that when certain leaves fell into boiling water, a fragrant and restorative drink resulted. Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.

The history of coffee has been recorded as far back as the ninth century. During that time, coffee beans were available only in their place of origin, Ethiopia. Legends trace the discovery of coffee either to a Sufi dervish named Omar, or to a goatherder named Kaldi, who observed goats become elated and sleepless at night after grazing on coffee shrubs and, upon trying the berries the goats had been eating, experienced the same vitality. The earliest literary mention of coffee may be a reference to Bunchum in the works of the 9th-century Persian physician al-Razi. The first reliable record of the use of coffee outside Ethiopia comes from Aden, in 1451. The appreciation of coffee as a beverage in Europe dates from the 17th century. The first coffee house in Venice opened some time in the late 1640s. In Britain, the first coffee house was opened in Oxford in 1650. They soon became popular throughout Western Europe, and played a significant role in social relations in the 17th and 18th centuries.

Use of the kola nut, like the coffee berry and tea leaf, appears to have ancient origins. It is chewed in many West African cultures, individually or in a social setting, to restore vitality and ease hunger pangs. In 1911, kola became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging the caffeine in its drink was injurious to health. Although the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of habit-forming and deleterious substances, which must be listed on a product's label.

The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated to 600 BCE. In the New World, chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with vanilla, chile pepper, and achiote. Xocolatl was believed to fight fatigue, a belief probably attributable to the theobromine and caffeine content. Chocolate was an important luxury good throughout pre-Columbian Mesoamerica, and cocoa beans were often used as currency.

Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known as black bean.

The leaves and stems of the yaupon holly (Ilex vomitoria) were used by Native Americans to brew a tea called asi or the black drink. Archaeologists have found evidence of this use stretch back far into antiquity, possibly dating to Late Archaic times.


Discovery

In 1819, the German chemist Friedlieb Ferdinand Runge isolated relatively pure caffeine for the first time; he called it Kaffebase (i.e., a base that exists in coffee). In 1821, caffeine was isolated both by French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre-Joseph Pelletier and Joseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal. Furthermore, Berzelius stated the French chemists had made their discoveries independently of any knowledge of Runge's or each other's work.

Pelletier's article on caffeine was the first to use the term in print (in the French form Caféine). It corroborates Berzelius's account:

Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period – while they were searching for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the same family as the cinchona [quinine] tree – on their part, Mssrs. Pelletier and Caventou obtained caffeine; but because their research had a different goal and because their research had not been finished, they left priority on this subject to Mr. Robiquet. We do not know why Mr. Robiquet has not published the analysis of coffee which he read to the Pharmacy Society. Its publication would have allowed us to make caffeine better known and give us accurate ideas of coffee's composition ...


German chemist Hermann Emil Fischer (1852–1919) first synthesized caffeine from raw materials in 1895 and two years later, he also derived the structural formula of the compound.

Robiquet was one of the first to isolate and describe the properties of pure caffeine while Pelletier was the first to perform an elemental analysis.

Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating: However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris. According to Runge, he did this at the behest of Johann Wolfgang von Goethe. In 1827, M. Oudry isolated theine from tea, but it was later proved by Mulder and by Carl Jobst that theine was the same as caffeine. The structure of caffeine was elucidated near the end of the 19th century by Hermann Emil Fischer, who was also the first to achieve its total synthesis. This was part of the work for which Fischer was awarded the Nobel Prize in 1902.


Legality

Today, caffeine is legal and available in many forms in all jurisdictions.

Historically, coffee and thus caffeine was illegal for some classes in Mecca in parts of the 16th century, and in the Ottoman empire. Charles II of England tried to ban it in 1676, Frederic II of Prussia banned it in 1777, and coffee was banned in Sweden in the years 1756–1769, 1794–1796, 1799–1802, and 1817–1823. The bans on coffee have often had religious, economic, or political reasons rather than being based on concerns for the well-being of the population.


Religion

Some Seventh-day Adventists, Church of God (Restoration) adherents, and Christian Scientists do not consume caffeine. Some from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive. The Church of Jesus Christ of Latter-day Saints has said the following with regard to caffeinated beverages: With reference to cola drinks, the Church has never officially taken a position on this matter, but the leaders of the Church have advised, and we do now specifically advise, against the use of any drink containing harmful habit-forming drugs under circumstances that would result in acquiring the habit. Any beverage that contains ingredients harmful to the body should be avoided.

Gaudiya Vaishnavas generally also abstain from caffeine, as it is alleged to cloud the mind and over-stimulate the senses. To be initiated under a guru, one must have had no caffeine, alcohol, nicotine or other drugs, for at least a year.

People who refrain from consuming caffeine, for religious or other reasons, may instead use a substitute that performs a culturally similar role to coffee.

Caffeinated beverages are widely consumed by Muslims today; in the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden intoxicating beverages under Islamic dietary laws.

MDMA
MDMA (3,4-methylenedioxy-N-methylamphetamine) is an empathogenic drug of the phenethylamine and amphetamine classes of drugs. MDMA has become widely known as ecstasy (shortened to E, X, or XTC), usually referring to its street pill form, although this term may also include the presence of possible adulterants. The term mandy or molly colloquially refers to MDMA in powder or crystalline form, usually implying a higher level of purity.

MDMA can induce euphoria, a sense of intimacy with others, diminished anxiety, and mild psychedelia. Many studies, particularly in the fields of psychology and cognitive therapy, have suggested MDMA has therapeutic benefits and facilitates therapy sessions in certain individuals, a practice for which it had been formally used in the past. Clinical trials are now testing the therapeutic potential of MDMA for post-traumatic stress disorder, anxiety associated with terminal cancer and addiction.

MDMA is criminalized in most countries (though some civil society initiatives—such as the Global Commission on Drug Policy—consider educating the public about the drug more important than curtailing supply) and its possession, manufacture, or sale may result in criminal prosecution. Some limited exceptions exist for scientific and medical research. For 2008, the UN estimated between 10 and 25 million people globally used MDMA at least once in the past year. This was broadly similar to the number of cocaine, amphetamine, and opioid users, but far fewer than the global number of cannabis users. It is taken in a variety of contexts far removed from its roots in psychotherapeutic settings, and is commonly associated with dance parties (or raves) and electronic dance music.

Regulatory authorities in several locations around the world have approved scientific studies administering MDMA to humans to examine its therapeutic potential and its effects.


Effects of MDMA on the human body



The effects of MDMA (or ecstasy) on the human brain and body are complex. The biochemical effects induced include serotonin, dopamine, and norepinephrine release, and can act directly on a number of receptors, including α2-adrenergic (adrenaline) and 5-HT2A (serotonin) receptors. (DHEA), and the antidiuretic hormone vasopressin (which may be important in its occasional production of water intoxication or hyponatremia).

It is not understood how the chemical effects of MDMA induce its psychoactive effects. Most explanations focus on serotonin release. MDMA causes serotonin vesicles in the neurons to release quantities of serotonin into the synapses. Studies using pretreatment with an SSRI to block the ability of MDMA to release serotonin in volunteers suggest serotonin release is necessary for most psychoactive effects of MDMA in humans. Released serotonin stimulates several receptors that are believed to contribute to the experiential effects of MDMA. Laboratory rodent experiments have shown MDMA to activate oxytocin-containing neurons in the hypothalamus by stimulating 5-HT1A receptors. This appears to contribute to some of the social effects of MDMA: upon administering a drug that blocked brain receptors for oxytocin, the effects of the drug on social behavior were reduced. A second serotonin receptor, 5-HT2A receptors (which are important for the effects of hallucinogens), makes mild contributions to MDMA effects. When the receptor was blocked, volunteers given MDMA reported decreases in MDMA-induced perceptual changes, emotional excitation, and acute adverse responses. In contrast, blocking these 5-HT2A receptors had little effect on MDMA-induced positive mood, well-being, extroversion, and most short-term sequelae. One possible explanation for some of these 5-HTA-mediated effects is that 5-HT2A stimulation inhibits dopamine release.

Although serotonin is important to the effects of MDMA, other drugs that release serotonin, such as fenfluramine, do not have effects like MDMA. This indicates that other neurochemical systems must be important for the MDMA experience. In addition to serotonin, dopamine and noradrenaline may play important roles in producing MDMA effects. The dopaminergic D2 receptor antagonist haloperidol selectively reduced the euphoric effects of MDMA in volunteers while increasing feelings of anxiety. Although not yet examined in humans, several studies in rodents indicate the noradrenergic mechanisms contribute to the stimulating effects of MDMA. Finally, currently unexplored effects of MDMA may turn out to be important, such as trace amine receptors.

The effects of MDMA on regional cerebral blood flow (CBF) have been studied in humans using [H215O]-Positron Emission Tomography (PET) MDMA was found to produce alteration of brain activity in cortical, limbic, and paralimbic structures. The dose of MDMA, 1.7 mg/kg, was psychoactive and participants reported heightened mood, increased extroversion, feelings of altered reality, and mild perceptual alterations. Feelings of extroversion correlated with CBF in the temporal cortex, amygdala, and orbitofrontal cortex.


Subjective effects



Short-term experiential effects, which tend to last less than 4 hours, include:

Mental and physical euphoria
A sense of general well-being and contentedness
Decreased negative emotion and behavior such as stress, anxiety, fear, and paranoia
Increased sociability and feelings of communication being easy or simple
Increased urge to communicate with others
Increased empathy and feelings of closeness or connection with others
Reduced insecurity, defensiveness, and fear of emotional injury
Decreased irritability, aggression, anger, and jealousy
A sense of increased insightfulness and introspection
Mild psychedelia (colors and sounds are enhanced, mild closed-eye visuals, improved pattern recognition, etc.)
Enhanced tactile sensations (touching, hugging, and sex)

Effects beginning after the main effects of MDMA have ended, which can last several days, include:

Lowered mood or even depression (comedown) after the effects have worn off
Increased anxiety, stress, and other negative emotions
Residual feelings of empathy, emotional sensitivity, and a sense of closeness to others (afterglow)


Other short-term effects



Acute physiological effects include:

Increased heart rate and blood pressure
Increased body temperature
Increased perspiration and sweating
Impaired Speech
Pupil dilation
Blurred vision
Nystagmus (rapid involuntary eye movements and jittering)
Trismus (difficulty opening the mouth widely) and bruxism (grinding and clenching of the teeth)
Difficulty sleeping
Loss of appetite
Nausea and emesis
Urinary retention
In males, possible erectile dysfunction


Adverse effects



Also, serious adverse events in MDMA users may be an interaction of the drug with a preexisting medical condition. Risk of adverse event after MDMA consumption is thought to be increased by preexisting cardiovascular problems, such as cardiomyopathy, hypertension, viral myocarditis, and congenital cardiac conduction abnormalities (such as Wolff–Parkinson–White, Romano–Ward, Brugada, and Jervell and Lange–Nielsen Syndromes).

Serious adverse events in MDMA users may also be caused by drugs sold as ecstasy, but which are not actually MDMA. Dangerous overheating, sometimes fatal, is associated with drugs such as PMA or 4-MTA. To help mitigate risks associated with the consumption of MDMA, certain organizations have created screening test kits to prevent the consumption of more harmful substances such as PMA, Methamphetamine, 2C analogs, BZP and TFMPP.


Hyponatremia



An important cause of death following MDMA use is hyponatremia, low blood sodium levels as a result of drinking too much water. While it is important to avoid becoming dehydrated, especially when out dancing in a hot environment, there have been a number of users suffering from water intoxication and associated hyponatremia (dilution of the blood that can cause swelling of the brain). Although many cases of this clearly involved individuals drinking large amounts of water, there are cases where there is no evidence of excessive water consumption. Their cases may be caused by MDMA inducing release of the antidiuretic hormone vasopressin by the pituitary gland. The action of vasopressin on the renal tubules leads to the retention of water, resulting in users producing less urine. (This is unrelated to having difficulty passing urine, a phenomenon known colloquially as E-wee). Hyponatremia also affects marathon runners and bodybuilders, who have been known to die from similar causes, as a result of drinking too much water and sweating out too much salt. It affects women more than men.

Hyponatremia is preventable by drinking fluid containing sodium, such as that contained in sports drinks (typically ~20mM NaCl).


Hyperthermia



The primary acute risks of taking MDMA resemble those of other stimulant amphetamines. The second most important cause of death from MDMA use is hyperthermia, core body temperature rising too high until the major organs shut down at about 42°C. This is comparatively more problematic than blood salt imbalance, harder to treat and to avoid. MDMA-related hyperthermia may occur as a symptom of serotonin syndrome, which is where too much serotonin is released into the brain. This can occur with MDMA if too much 5HTP or other serotonergic drugs are consumed together. 50–200 mg of 5HTP is believed by some users to make MDMA work better and last longer, but anecdotally more than 300 mg 5HTP may increase risk of serotonin syndrome, which can lead into lethal hyperthermia if it becomes too severe. It has been suggested that hyperthyroidism may also increase risk of MDMA-related hyperthermia.

Note that this is different from normal hyperthermia. Dance parties are an obvious hyperthermia risk environment, the venue often being hot and crowded, and the attending public dancing whilst on stimulant drugs. Ideally the temperature inside the dance rooms should be maintained in the range 24–27°C; MDMA affects the body's ability to regulate temperature and it is easy to become either too hot or too cold if the temperature is outside of this range.

Mild hyperthermia and/or dehydration can occur from dancing too long, and users may recover with administration of fluids and rest in a cooler environment. However, if the user expresses concern about how hot they feel, or if their body temperature is still rising even when they have stopped dancing and are in a cooler environment, and their skin is hot and dry to the touch, then they may be developing more dangerous drug-induced hyperthermia, and these cases should be taken to and handled by a medical professional immediately. Treatment is most effective the sooner it is given, as with all adverse drug reactions. Hyperthermia is a particular concern if MDMA use is combined with other substances, such as 5HTP, or if additional stimulants are involved, such as methamphetamine or cocaine. MDMA is also implicated in affecting the mechanism of uncoupling protein (UCP), more specifically UCP3 in mitochondria which can lead to the abnormal thermogenic response.

In animal studies, a combination of prazosin (α1 adrenergic antagonist) and pindolol (5-HT1A antagonist/beta blocker) quickly and completely terminates drug-induced hyperthermia. Another drug, the migraine medicine pizotyline has also been shown to be useful in treating MDMA overdose in animals. However, neither of these treatments are approved for use in humans.

MDMA appears to decrease heat loss in the body by causing constriction of blood vessels near the skin. In addition, it can increase heat production by muscles and the brain. These effects may be amplified in people who become dehydrated and are therefore unable to cool by sweating. On top of this, MDMA can mask the body's normal thirst and exhaustion responses, particularly if a user is dancing or is otherwise physically active for long periods of time without hydration. Because of these effects, MDMA can temporarily reduce the body's ability to regulate its core temperature so that high-temperature surroundings (e.g. clubs) combined with physical exertion may lead to hyperpyrexia if precautions are not taken to remain cool. Sustained hyperpyrexia may lead to rhabdomyolysis, which in turn can cause renal failure and death. Depending on the initial cause of rhabdomyolysis, it may be successfully treated with dantrolene if diagnosed early enough, but often the characteristic symptoms may not be apparent until the condition is already severe.


Treatment

MDMA-induced hyperthermia may be treated with dantrolene.


Overdose



Due to the difference between the recreational dose and the lethality dose, it is extremely rare for a death to be accredited just to the consumption of MDMA. While a typical recreational dose is roughly 100–150 mg (often being measured by eye and dealt with as fractions of a gram), this dose is often then repeated but remains well below the lethal dose. Consumption of the drug can be self-reinforcing while under the influence, and overdoses can occur.

The standard treatment for MDMA overdose given in hospitals includes a range of drugs such as cyproheptadine or chlorpromazine but these are often of limited efficacy. MDMA overdose mainly results in hyperthermia and hyponatremia, which leads onto convulsions from the hyponatremia and rhabdomyolysis (toxic muscle breakdown) from the hyperthermia. These complications can be treated; benzodiazepines such as diazepam or lorazepam are used to control convulsions and dantrolene blocks rhabdomyolysis.

It's been argued that the seriousness of the effects can be dependent on environmental factors other than the drug concentration, as blood concentrations of the drug spanned a large range in cases of death in MDMA users. This not-with-standing, most of the cases of serious toxicity or fatality have involved blood levels... up to 40 times higher than the usual recreational range.

Quoted from Dr. Julie Holland: Not only are MDMA related cases a small percentage of all drug-related emergency room visits, but a large percentage of MDMA cases are not life-threatening. In a recent study conducted by the physicians in the Emergency Department of Bellevue, (Rella, Int J Med Toxicol 2000; 3(5): 28) regional hospital ecstasy cases phoned into the New York City poison control center were analyzed. There were 191 cases reported during the years 1993 to 1999 inclusive. This is a rate of fewer than thirty cases per year. 139 cases (73%%) were mild and experienced minor or no toxicity. The most commonly reported symptoms were increased heart rate (22%%), agitation (19%%), and nausea and vomiting (12%%). In these seven years, only one ecstasy-related death was reported, which was due to hyperthermia, or overheating.


Other adverse effects



MDMA users almost always experience bruxism (teeth grinding) and trismus (jaw clenching) as a short-term effect from the drug. Many users of MDMA alleviate this by using chewing gum, or chewing on improvised mouth guards (such as a small plastic glow stick or pacifier). Temporary jaw ache often results from jaw clenching or excessive chewing. Some users consume supplemental magnesium tablets to relax the jaw muscles and relieve clenching, although this practice has not been formally studied. In extreme cases, MDMA use has been associated with excessive wear of teeth and resulting dental problems.

Liver damage, which may have an immunological cause, has been seen in a small number of users. It is not clear to what extent liver toxicity is caused by MDMA or other compounds found in ecstasy tablets. Animal studies suggest MDMA can cause liver damage and that the risk and extent of liver damage is increased by high body temperature.

While there has been an urban legend that having an allergy to penicillin or related antibiotics means one is allergic to MDMA, this myth is baseless, as the two drugs are far too different for an allergy to one to translate into an allergy to the other.

In very rare cases, MDMA has been associated with serious neurological problems such as subarachnoid hemorrhage, intracranial bleeding, or cerebral infarction. Similar problems have been noted with amphetamines. The mechanisms are thought to involve the short-term hypertension leading to damage of cerebral blood vessels, especially in patients with pre-existing conditions such as arteriovenous malformations or cerebral angiomas.

While users sometimes report increased sexual desire, there are many reports of difficulty achieving both erection and orgasm while on the drug. It has been said that, [MDMA] is a love drug but not a sex drug for most people. This is the rationale behind the use of sextasy (combining MDMA with Viagra).


Long-term adverse effects



Research on possible long-term adverse effects of MDMA has mainly focused on two areas. The first area is possible serotonergic neurotoxicity. The second area is psychiatric and behavioral problems that might result from MDMA use. These possible adverse effects may be independent. Studies finding serotonergic changes do not always find cognitive-behavioral changes and studies finding cognitive-behavioral changes do not always find serotonergic changes.

In addition to these main areas of research, there have been a number of animal studies suggesting MDMA can cause other possible neurological changes, including apoptosis, non-serotonergic neurotoxicity in the somatosensory cortex, and increased expression and altered processing of amyloid precursor protein.


Serotonergic changes



Experiments indicate that both moderate and high dose or rapidly repeated MDMA exposure may lead to long-lasting changes in neurons that make serotonin. Serotonergic changes have been demonstrated experimentally in the brains of all mammalian species studied, with most studies involving rats. In these studies, the brains of animals who are given high or repeated doses of MDMA show long-term decreases in all measures of serotonergic functioning, including concentrations of serotonin, tryptophan hydroxylase, and binding of the serotonin transporter protein. Although measures of serotonin are decreased, there are no decreases in the number of cells in the dorsal raphe, which indicates that the serotonin neurons have not died. Limited studies attempting to stain and photograph serotonergic axons shortly after high-dose MDMA exposure have reported that axons appear swollen and misshapen, as if they might be degenerating. However, few studies have attempted to stain and examine axons and with the measures commonly used in MDMA studies it is difficult or impossible to distinguish axon loss from decreases in production of markers of serotonin.

Animal studies show that there is recovery of serotonergic markers. However, if axons are actually regrowing, there is no assurance that they will reform their original connections. While rats show extensive recovery that sometimes appears complete, some primate studies show evidence of lasting alterations in serotonergic measures. Human studies, discussed below, show recovery, but these studies use indirect measures that may lack sensitivity for detecting subtle changes.

It's not known what dose(s) of MDMA would produce similar toxic effects in humans. This is because there are some difficulties in translating animal MDMA toxicity studies to humans. Firstly, it is difficult to equate rat doses to human doses, because rats metabolize MDMA twice as fast as humans and often larger doses or multiple doses are administered to simulate human plasma levels. Second, if the neurotoxicity of MDMA depends on its metabolites (Jones 2004), it may be difficult or impossible to translate an MDMA dose between species since different species metabolize MDMA to different extents. Therefore, it is difficult to say what dose in humans would produce the effects seen in animals.

Keeping these limitations in mind, comparisons of MDMA exposures can be made between animal neurotoxicity studies and human clinical studies. One (uncertain) estimate suggests that the neurotoxic dose may be only moderately higher than amounts given in clinical studies (1.5 or 1.7 mg/kg, about 100 or 120 mg). That published comparison was made based on data from rats.

Further comparisons can be made using monkey data. In a recent study by Mechan et al. (2006), the lowest repeated dose regimen that produced serotonergic effects, detectable after 2 weeks, in squirrel monkeys was 2.4 mg/kg given orally three times in a row (every 3 hours). The peak plasma MDMA concentrations seen after that dose was 787 ± 129 ng/ml (mean ± SEM, range: 654 to 1046 ng/ml) and the Area Under the Concentration vs. Time-Curve (AUC, a measure of overall drug exposure) was 3451 ± 103 hr*ng/ml. In comparison, 1.6 mg/kg oral (112 mg in a 70 kg / person) in humans produces peak MDMA concentrations of 291.8 ± 76.5 ng/ml (range: 190 - 465 ng/ml) and an AUC of 3485.3 ± 760.1 hr*ng/ml (Kolbrich et al. 2008). Thus, a typical human dose produces peak MDMA concentrations that are about 37%% of a known neurotoxic dose and has a very similar AUC. Because MDMA has nonlinear kinetics, it is likely that fewer than three of these doses would be needed to produce an exposure in humans greater than the dose schedule that produced decreased brain serotonin and decreased serotonin transporter binding in monkeys.


Mechanisms of serotonergic changes



The mechanism proposed for this apparent neurotoxicity involves the induction of oxidative stress. This stress results from an increase in free radicals and a decrease in antioxidants in the brain. (Shankaran, 2001) Oxidation is part of the normal metabolic processes of the body. As the cell goes about its life, by-products called oxidative radicals are formed, also called free radicals. These molecules have an unpaired electron that makes them highly reactive. They pull strongly on the electrons of neighboring molecules and destabilize the electrical balance of those molecules, sometimes causing those molecules to fall apart. This can become a chain reaction.

In normal functioning, there are antioxidants in the system that act as free radical scavengers. These are molecules with an extra electron that they are willing to give up to the free radicals, making both the free radical and the antioxidant more stable. MDMA rapidly increases the levels of free radicals in the system, which is thought to overwhelm the reserves of scavengers. The radicals then damage cell walls, reduce the flexibility of blood vessels, destroy enzymes, and cause other molecular damage in the neurological pathways. (Erowid, 2001) It has been shown that MDMA's neurotoxic effects in rodents are increased by a hyperthermic environment and decreased by a hypothermic one. (Yeh, 1997).

Studies have suggested that the neurotoxic molecules are not hydroxyl free radicals, but superoxide free radicals. When rats are injected with salicylate, a molecule that scavenges hydroxyl free radicals, the neurotoxic effects of MDMA are not attenuated, but actually potentiated. Further evidence of this superoxide theory comes from the observation that CuZn-superoxide dismutase transgenic mice (mice with excess human antioxidant enzyme) demonstrate neuroprotective mechanisms that protect the mice from MDMA-induced depletion of 5-HT (serotonin) and 5-HIAA and lethal effects. (Baggott, 2001 and Yeh, 1997)

MDMA itself does not seem to be neurotoxic as infusing it into an animal's brain does not produce long-term serotonergic changes. This suggests that another molecule may be triggering the oxidative stress. Earlier scientists have suggested that dopamine might be important for initiating the cascade of oxidative stress. However, it needs to be a chemical which is not produced in the brain, but produced systemically, so this seems to rule out dopamine. More recent scientists suggest an MDMA metabolite (such as 3,4-dihydroxy-methamphetamine) may be responsible.


Possible neuroprotective strategies



There are a number of factors that have been shown to protect animals from long-term MDMA-induced serotonin changes. These include dose, temperature, antioxidants, and SSRIs. Some MDMA users have attempted to use analogous strategies to decrease their risks of long-term serotonin changes, although there is uncertainty as to how well this works in people.

The most obvious strategy is reducing dose. Long-term serotonergic changes are dose dependent in animals. Taking higher or repeated doses of MDMA is therefore likely to increase chances of similar changes in people. Although the threshold dose to cause toxicity is unknown in humans, lower doses are almost certainly less risky.

Studies in rats also find that environments or activities that increase the animals' body temperature increase serotonergic changes. However, this finding has not been replicated in primates, possibly because rodents are less able to regulate body temperature than primates. Nonetheless, it is possible that higher body temperature also increases serotonergic changes in people.

Antioxidants may decrease possible MDMA-induced serotonergic changes. Studies in rats have shown that injections of ascorbic acid, alpha lipoic acid, or some other radical scavengers are effective in reducing oxidative stress caused by MDMA. (Erowid, 2001) It has been speculated that humans may be able to similarly achieve protection using a combination of antioxidants, such as Vitamin A, C, and E or multivitamins including selenium, riboflavin, zinc, carotenoids, etc. may help reduce oxidative damage. No published studies have confirmed that this works. In addition, many of these vitamins, though, are water soluble, and are quickly excreted from the body. The typical MDMA user is psychoactive for 4–6 hours and may not have an appetite from the time of taking until the following sleep cycle or many hours later. Damage occurs in the absence of these antioxidants.

There are problems in trying to translate studies of neuroprotection with antioxidants from animal studies to humans. The effective doses of antioxidants given to these animals are much higher than humans would ever take both in its method of administration (injected vs. oral) and in its dosage. Both the neurotoxic and neuroprotective effects may be maximized in these animal studies, and it is not possible to know what doses or patterns of use (if any) would produce the same effects in people.

Selective serotonin reuptake inhibitors (SSRIs) have been shown to decrease or block MDMA neurotoxicity in rodents, even if they are given several hours after MDMA. Because of this, some MDMA users administer an SSRI while, or shortly after taking MDMA, in an attempt to prevent possible neurotoxicity. These SSRIs are typically antidepressants such as fluoxetine or sertraline. The theory of some scientists is that SSRIs prevent dopamine or a neurotoxic MDMA metabolite from entering through the serotonin reuptake transporter, where it is theorized that it may contribute to formation of reactive oxygen species, including hydrogen peroxide. There are several concerns with taking SSRIs with MDMA. On a practical level, administration of SSRIs will block the desired effects of the drug if taken too early. This blocking effect can last several weeks, depending on the half-life of the SSRI. In addition, MDMA and the SSRI will often mutually reduce each other's metabolism, causing them to last longer in the body. Theoretically, this might increase risk of overdosing on the SSRI, leading to serotonin syndrome. Although this appears to occur rarely (if ever), it is considered a theoretical possibility.

More significant risks occur if MDMA is taken with some other prescription drugs, including antidepressants that act as monoamine oxidase inhibitor. This can lead to serotonin syndrome and the possibility of life-threatening hypertension.

Many users also attempt to replenish the hypothesized deficit of serotonin that is thought to follow the use of MDMA by administering 5-HTP, in an attempt to reduce the depressed mood and unpleasant symptoms in the days following MDMA usage (including the immediate come-down and what is known as suicide Tuesday or mid-week blues). The serotonin precursor 5-HTP, which is commercially available as a dietary supplement, supplies the user with more of the raw materials to synthesize the neurotransmitter, theoretically reducing the negative psychological effects of depleted serotonin. (Note that normal dietary sources of serotonin precursors may have less than normal effects if tryptophan hydroxylase levels have been reduced by MDMA.) Varied reports indicate that the perceived impact of pre-loading is dependent upon a number of factors and while it has not been shown to reliably increase the subjective effects of MDMA, your mileage may vary.


Evidence for serotonergic changes in humans



Studies have used positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging methods to estimate brain serotonin transporter levels in MDMA users. These studies have found reduced levels of the transporter in recently abstinent MDMA users as well as evidence of partial or full recovery with prolonged abstinence. However, the sensitivity of these methods is unknown and changes may not have been detected. Three studies of 5-HT2A receptors in human MDMA users have been published by one group of researchers (Reneman and colleagues). Together, these studies find possibly reduced receptor binding during active MDMA use and increased receptor binding in longer-abstinent subjects. The authors argue that long-lasting reductions in 5-HT release may have caused compensatory up-regulation of 5-HT2A receptors. Other studies have measured cerebrospinal fluid concentrations of the serotonin metabolite 5HIAA. Three of four published studies have reported concentrations to be lower in MDMA users than non-users.

One difficulty in interpreting these studies is that it is difficult to know if serotonergic differences predated MDMA use. In addition, none of these studies can address whether any changes are neurotoxicity proper or neuroadaptation. A recent review concluded that the current state of neuroimaging in human MDMA users do not permit conclusions regarding the long-term effects of MDMA exposure.

Although they are often studied in the same people or animals, possible serotonergic changes may have different risk, mechanisms, and recovery compared to possible cognitive and behavioral enhancing changes occurring during MDMA exposure. Studies in animals and mankind have generally failed to correlate these two domains.


Psychiatric and behavioral changes



Some studies find that repeated MDMA use may lead to subtle changes in learning, memory, attention, executive function, mood, and decision making. Considerable research has been done into these possible cognitive-behavioral deficits but studies are inconclusive. Most are retrospective, that is, they study people after they started using MDMA. This makes it difficult to know if differences between users and non-users were preexisting.

There does not seem to be a single type of cognitive task that is consistently altered in the different studies. Tasks that have shown differences include ones measuring attention, learning, memory, and executive function. Many of the findings, which are more commonly reported in people with more extensive MDMA use histories (or even abuse diagnoses), may simply reflect preexisting differences between people who are drawn to use drugs like MDMA frequently and those who do not.

In addition, mood is sometimes found to be worse and impulsivity greater in MDMA users. At least two meta-analyses of these studies have been completed (Morgan 2000; Sumnall & Cole 2005). Morgan's analysis of 17 studies showed that MDMA users had a slight tendency to be more impulsive and have lower mood than controls. Sumnall and Cole's analysis showed a slight increase in the prevalence of depressive symptoms in MDMA users over controls. (Mood measured in these studies does not indicate clinical levels of depression, which has not been associated with MDMA use.) Of course, studies like these raise a cause-consequence question: did these impulsive and depressed people use MDMA to self-medicate or did otherwise normal people become depressed and impulsive after using MDMA. This question has not been conclusively answered and both possibilities may be true in individual cases.

There are a growing number of longitudinal or prospective studies, looking at users and nonusers at several points in time. Published prospective studies tend to report subtle difference between users and nonusers with performance within normal range. These difference tend to persist (Reneman et al. 2006; Gouzoulis-Mayfrank et al. 2005; Thomasius et al. 2006) or increase across time (Zakzanis and Young 2001; Zakzanis and Campbell 2006). While persisting differences are consistent with differences predating MDMA use, increases may indicate worsening due to drug exposure.

A recent study (the NeXT Netherlands XTC toxicity study) prospectively examined 25 people before and after their first episode of MDMA use (mean 2.0 ± 1.4 ecstasy pills, on average 11.1 ± 12.9 weeks since last MDMA use). The study measured working memory, selective attention, and associative memory using fMRI. No significant effects were found of the reportedly modest dose(s) of MDMA on any of these measures, suggesting that the first few exposures to MDMA typically do not cause significant residual toxicity. Thus, if MDMA does cause cognitive-behavioral changes, it would likely require repeated use for these changes to occur (or become detectable). Contrary to this another recent report has shown that a single exposure to MDMA can result in cognitive-behavioral changes. The study took a group of people who have never used MDMA and had them perform cognitive tests. The participants were then exposed to a low dose of MDMA and underwent the same cognitive tests three years later. It was found that scores on immediate and delayed verbal recall and verbal recognition were significantly lower in the group of incident MDMA users compared with persistent MDMA-naive subjects. The authors did recognize there were limitations to their study but it shows that MDMA most likely does cause cognitive-behavioral effects after one exposure.

In addition to concerns about neurotoxicity, several published reports have described hallucinogen persisting perception disorder in MDMA users. This appears to be very rare and published cases have been complicated by use of other drugs, in concurrence with MDMA use.


Addiction and tolerance



The potential of MDMA to produce addiction is controversial. Some studies indicate that many users may be addicted, but this depends on the definition of addiction; while many MDMA users may take the drug regularly and develop significant tolerance to its effects, relatively few users exhibit cravings or physical symptoms of dependence, or find it difficult to stop using the drug when they decide to do so. Cottler et al. (2001) interviewed 52 users and found that 43%% met standard criteria for dependence. Tolerance and after effects (withdrawal effects) are symptoms of dependence for many drugs, but seem to occur in some MDMA users who are actually not dependent. For example, studies in Switzerland in which MDMA was given to people who had never used it before documented after effects. When people are classified as addicted to MDMA, it is not clear if that indicates a difficulty in quitting the drug. In a prospective study in Germany, many who were initially categorized as addicted, spontaneously 'improved' without any treatment for the alleged addiction. Given the complexities in classifying MDMA users as addicted, conclusions about the addictive potential of MDMA are less reliable than those about nicotine addiction.


Retracted article on MDMA-induced dopamine neurotoxicity in primates



In a retracted article on toxicity of MDMA on dopamine cells, a research team led by Dr. George A. Ricaurte at Johns Hopkins University implicated MDMA as a cause of Parkinson's-like brain abnormalities in monkeys, suggesting that a single use of MDMA caused permanent and serious damage to dopamine neurons. This controversial finding was subsequently retracted with the researchers stating that they had inadvertently injected their experimental animals with methamphetamine instead of MDMA.


Drug interactions



A number of reported potentially dangerous possible interactions occur between MDMA and other drugs, including serotonergic drugs. Several cases have been reported of death in individuals who ingested MDMA while taking ritonavir (Norvir), which inhibits multiple CYP450 enzymes. Toxicity or death has also been reported in people who took MDMA in combination with certain monoamine oxidase inhibitors, such as phenelzine (Nardil), tranylcypromine (Parnate), or moclobemide (Aurorix, Manerix). Conversely, MAOB inhibitors such as selegiline (Deprenyl; Eldepryl, Zelapar, Emsam) do not seem to carry these risks when taken at selective doses, and have been used to completely block neurotoxicity in rats.


Sassafras oil



Commercial sassafras oil generally is a byproduct of camphor production in Asia or comes from related trees in Brazil. Safrole is a precursor for the clandestine manufacture of MDMA, and as such, its transport is monitored internationally. Roots of Sassafras can also be steeped to make tea and were used in the flavoring of traditional root beer until being banned for mass production by the FDA. Laboratory animals that were given oral doses of sassafras tea or sassafras oil that contained large doses of safrole developed permanent liver damage or various types of cancer. In humans, liver damage can take years to develop, and it may not have obvious signs. While sassafras oil is an important ingredient in clandestine manufacture of MDMA, MDMA itself does not contain any sassafras oil..


Chemistry



Safrole, a colorless or slightly yellow oily liquid, extracted from the root-bark or the fruit of the sassafras tree is the primary precursor for all manufacture of MDMA. There are numerous synthetic methods available in the literature to convert safrole into MDMA via different intermediates. One common route is via the MDP2P (3,4-methylenedioxyphenyl-2-propanone, also known as piperonyl acetone) intermediate, which can be produced in at least two different ways. One method is to isomerize safrole to isosafrole in the presence of a strong base, and then oxidize isosafrole to MDP2P. Another, reportedly better, method is to make use of the Wacker process to oxidize safrole directly to the MDP2P (3,4-methylenedioxy phenyl-2-propanone) intermediate. This can be done with a palladium catalyst. Once the MDP2P intermediate has been prepared, a reductive amination leads to MDMA, a racemate {1:1 mixture of (R)1(benzo[d][1,3]dioxol-5-yl)N-methylpropan-2-amine and (S)-1(benzo[d][1,3]dioxol-5-yl)-N-methylpropan-2-amine}. Another method for the synthesis of racemic MDMA is addition of hydrogen bromide to safrole and reaction of the adduct with methylamine. Safrole is not required for MDMA production, and other precursor chemicals are often used instead, for example piperonal.

Relatively small quantities of essential oil are required to make large amounts of MDMA. The essential oil of Ocotea cymbarum typically contains between 80 and 94%% safrole. This would allow 500 ml of the oil, which retails at between $20 and $100, to be used to produce between 150 and 340 grams of MDMA.


Pharmacology



MDMA acts as a releasing agent of serotonin, norepinephrine, and dopamine. It enters neurons via carriage by the monoamine transporters. Once inside, MDMA inhibits the vesicular monoamine transporter, which results in increased concentrations of serotonin, norepinephrine, and dopamine in the cytoplasm, and induces their release by reversing their respective transporters through a process known as phosphorylation.

MDMA has been identified as a potent agonist of TAAR1, a newly discovered GPCR important for regulation of monoaminergic systems in the brain. Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits transporter function. These effects increase monoamine efflux and prolong the amount of time monoamines remain in the synapse. It also acts as a weak 5-HT1 and 5-HT2 receptor agonist, and its more efficacious metabolite MDA likely augments this action.

MDMA's unusual entactogenic effects have been hypothesized to be, at least partly, the result of indirect oxytocin secretion via activation of the serotonin system. Oxytocin is a hormone released following events such as hugging, orgasm, and childbirth, and is thought to facilitate bonding and the establishment of trust. Based on studies in rats, MDMA is believed to cause the release of oxytocin, at least in part, by both directly and indirectly agonizing the serotonin 5-HT1A receptor. A placebo-controlled study in 15 human volunteers found 100 mg MDMA increased blood levels of oxytocin, and the amount of oxytocin increase was correlated with the subjective prosocial effects of MDMA.

Three neurobiological mechanisms for the therapeutic effects of MDMA have been suggested: 1) MDMA increases oxytocin levels, which may strengthen the therapeutic alliance; 2) MDMA increases ventromedial prefrontal activity and decreases amygdala activity, which may improve emotional regulation and decrease avoidance, and 3) MDMA increases norepinephrine (NE) release and circulating cortisol levels, which may facilitate emotional engagement and enhance extinction of learned fear associations.


Pharmacokinetics



MDMA reaches maximal concentrations in the blood stream between 1.5 and 3 hr after ingestion. It is then slowly metabolized and excreted, with levels of MDMA and its metabolites decreasing to half their peak concentration over approximately 8 hours. Thus, there are still high MDMA levels in the body when the experiential effects have mostly ended, indicating acute tolerance has developed to the actions of MDMA. Taking additional supplements of MDMA at this point, therefore, produces higher concentrations of MDMA in the blood and brain than might be expected based on the perceived effects.

Metabolites of MDMA that have been identified in humans include 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxy-methamphetamine (HMMA), 4-hydroxy-3-methoxyamphetamine (HMA), 3,4-dihydroxyamphetamine (DHA) (also called alpha-methyldopamine (α-Me-DA)), 3,4-methylenedioxyphenylacetone (MDP2P), and 3,4-Methylenedioxy-N-hydroxyamphetamine (MDOH). The contributions of these metabolites to the psychoactive and toxic effects of MDMA are an area of active research. Sixty-five percent of MDMA is excreted unchanged in the urine (in addition, 7%% is metabolized into MDA) during the 24 hours after ingestion.

MDMA is known to be metabolized by two main metabolic pathways: (1) O-demethylenation followed by catechol-O-methyltransferase (COMT)-catalyzed methylation and/or glucuronide/sulfate conjugation; and (2) N-dealkylation, deamination, and oxidation to the corresponding benzoic acid derivatives conjugated with glycine. The metabolism may be primarily by cytochrome P450 (CYP450) enzymes (CYP2D6 (in humans, but CYP2D1 in mice), and CYP3A4) and COMT. Complex, nonlinear pharmacokinetics arise via autoinhibition of CYP2D6 and CYP2D8, resulting in zeroth order kinetics at higher doses. It is thought that this can result in sustained and higher concentrations of MDMA if the user takes consecutive doses of the drug.

Because the enzyme CYP2D6 is deficient or totally absent in some people, it was once hypothesized that these people might have elevated risk when taking MDMA. However, there is still no evidence for this theory and available evidence argues against it. It is now thought that the contribution of CYP2D6 to MDMA metabolism in humans is less than 30%% of the metabolism. Indeed, an individual lacking CYP2D6 was given MDMA in a controlled clinical setting and a larger study gave MDMA to healthy volunteers after inhibiting CYP2D6 with paroxetine. Lack of the enzyme caused a modest increase in drug exposure and decreases in some metabolites, but physical effects did not appear appreciably elevated. While there is little or no evidence that low CYP2D6 activity increases risks from MDMA, it is likely that MDMA-induced CYP2D inhibition will increase risk of those prescription drugs that are metabolized by this enzyme. MDMA-induced CYP2D inhibition appears to last for up to a week after MDMA exposure.

MDMA and metabolites are primarily excreted as conjugates, such as sulfates and glucuronides.

MDMA is a chiral compound and has been almost exclusively administered as a racemate. However, the two enantiomers have been shown to exhibit different kinetics. (S)-MDMA is more effective in eliciting 5-HT, NE, and DA release, while (D)-MDMA is overall less effective, and more selective for 5-HT and NE release (having only a very faint efficacy on DA release). The disposition of MDMA may also be stereoselective, with the S-enantiomer having a shorter elimination half-life and greater excretion than the R-enantiomer. Evidence suggests that the area under the blood plasma concentration versus time curve (AUC) was two to four times higher for the (R)-enantiomer than the (S)-enantiomer after a 40 mg oral dose in human volunteers. Likewise, the plasma half-life of (R)-MDMA was significantly longer than that of the (S)-enantiomer (5.8 ± 2.2 hours vs 3.6 ± 0.9 hours). However, because MDMA excretion and metabolism have nonlinear kinetics, the half-lives would be higher at more typical doses (100 mg is sometimes considered a typical dose). Given as the racemate MDMA has a half-life of around 8 hours.


Detection of use



MDMA and MDA may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or a sudden death. Some drug abuse screening programs rely on hair, saliva, or sweat as specimens. Most commercial amphetamine immunoassay screening tests cross-react significantly with MDMA or its major metabolites, but chromatographic techniques can easily distinguish and separately measure each of these substances. The concentrations of MDA in the blood or urine of a person who has taken only MDMA are, in general, less than 10%% those of the parent drug.


History



MDMA was first synthesized in 1912 by Merck chemist Anton Köllisch. At the time, Merck was interested in developing substances that stopped abnormal bleeding. Merck wanted to evade an existing patent, held by Bayer, for one such compound: hydrastinine. At the behest of his superiors Walther Beckh and Otto Wolfes, Köllisch developed a preparation of a hydrastinine analogue, methylhydrastinine. MDMA was an intermediate compound in the synthesis of methylhydrastinine, and Merck was not interested in its properties at the time. On 24 December 1912, Merck filed two patent applications that described the synthesis of MDMA and its subsequent conversion to methylhydrastinine.

Merck records indicate that its researchers returned to the compound sporadically. In 1927, Max Oberlin studied the pharmacology of MDMA and observed that its effects on blood sugar and smooth muscles were similar to ephedrine's. Researchers at Merck conducted experiments with MDMA in 1952 and 1959. In 1953 and 1954, the United States Army commissioned a study of toxicity and behavioral effects in animals of injected mescaline and several analogues, including MDMA. The Army experimented with MDMA as an interrogation tool in Project MKUltra. These originally classified investigations were declassified and published in 1973. The first scientific paper on MDMA appeared in 1958 in Yakugaku Zasshi, the Journal of the Pharmaceutical Society of Japan. In this paper, Yutaka Kasuya described the synthesis of MDMA, a part of his research on antispasmodics.

MDMA was being used recreationally in the United States by 1970. In the mid-1970s, Alexander Shulgin, then at University of California, Berkeley, heard from his students about unusual effects of MDMA; among others, the drug had helped one of them to overcome his stutter. Intrigued, Shulgin synthesized MDMA and tried it himself in 1976. Two years later, he and David E. Nichols published the first report on the drug's psychotropic effect in humans. They described altered state of consciousness with emotional and sensual overtones that can be compared to marijuana, and to psilocybin devoid of the hallucinatory component. Shulgin took to occasionally using MDMA for relaxation, referring to it as my low-calorie martini, and giving the drug to his friends, researchers, and other people whom he thought could benefit from it. One such person was psychotherapist Leo Zeff, who had been known to use psychedelics in his practice. Zeff was so impressed with the effects of MDMA that he came out of his semi-retirement to proselytize for it. Over the following years, Zeff traveled around the U.S. and occasionally to Europe, training other psychotherapists in the use of MDMA. Among underground psychotherapists, MDMA developed a reputation for enhancing communication during clinical sessions, reducing patients' psychological defenses, and increasing capacity for therapeutic introspection.

In the early 1980s in the U.S., MDMA rose to prominence as Adam in trendy nightclubs and gay dance clubs in the Dallas area. From there, use spread to raves in major cities around the country, and then to mainstream society. Ecstasy was recognized as slang for MDMA as early as June 1982. The drug was first proposed for scheduling by the Drug Enforcement Administration (DEA) in July 1984 and was classified as a Schedule I controlled substance in the U.S. on 31 May 1985.

In the late 1980s, MDMA began to be widely used in the UK and other parts of Europe, becoming an integral element of rave culture and other psychedelic-influenced music scenes. Spreading along with rave culture, illicit MDMA use became increasingly widespread among young adults in universities and later in high schools. MDMA became one of the four most widely used illicit drugs in the U.S., along with cocaine, heroin, and cannabis. According to some estimates as of 2004, only marijuana attracts more first time users in the U.S.

After MDMA was criminalized, most medical use stopped, although some therapists continued to prescribe the drug illegally. Later Charles Grob initiated an ascending-dose safety study in healthy volunteers. Subsequent legally approved MDMA studies in humans have taken place in the U.S. in Detroit (Wayne State University), Chicago (University of Chicago), San Francisco (UCSF and California Pacific Medical Center), Baltimore (NIDA–NIH Intramural Program), and South Carolina, as well as in Switzerland (University Hospital of Psychiatry, Zürich), the Netherlands (Maastricht University), and Spain (Universitat Autònoma de Barcelona).

In 2010, the BBC reported that use of MDMA had decreased in the UK in previous years. This is thought to be due to increased seizures and decreased production of the precursor chemicals used to manufacture MDMA. Unwitting substitution with other drugs, such as mephedrone and methamphetamine, as well as legal alternatives to MDMA, such as BZP, MDPV, and methylone, are also thought to have contributed to its decrease in popularity.


Legal status



MDMA is legally controlled in most of the world under the UN Convention on Psychotropic Substances and other international agreements, although exceptions exist for research and limited medical use. In general, the unlicensed use, sale or manufacture of MDMA are all criminal offenses.


United Kingdom



MDMA was made illegal in 1977 by a modification order to the existing Misuse of Drugs Act 1971. Although MDMA was not named explicitly in this legislation, the order extended the definition of Class A drugs to include various ring-substituted phenethylamines, thereby making it illegal to sell, buy, or possess the drug without a licence. Penalties include a maximum of seven years and/or unlimited fine for possession; life and/or unlimited fine for production or trafficking. See list of drugs illegal in the UK for more information. In February 2009 an official independent scientific advisory board to the UK government recommended that MDMA be re-classified to Class B, but this recommendation was immediately rejected by the government. This 2009 report on MDMA stated:

The original classification of MDMA in 1977 under the Misuse of Drugs Act 1971 as a Class A drug was carried out before it had become widely used and with limited knowledge of its pharmacology and toxicology. Since then use has increased enormously, despite it being a Class A drug. As a consequence, there is now much more evidence on which to base future policy decisions.... Recommendation 1: A harm minimisation approach to the widespread use of MDMA should be continued.... Recommendation 6: MDMA should be re-classified as a Class B drug.


In 2000, the UK Police Foundation issued the Runciman Report, which reviewed the medical and social harms of MDMA and recommended: Ecstasy and related compounds should be transferred from Class A to Class B. In 2002, the Home Affairs Committee of the UK House of Commons, issued a report, The Government's Drugs Policy: Is it working?, which also recommended that MDMA should be reclassified to a Class B drug. The UK government rejected both recommendations, saying that re-classification of MDMA would not be considered without a recommendation from the Advisory Council on the Misuse of Drugs, the official UK scientific advisory board on drug abuse issues.

In February 2009, the UK Advisory Council on the Misuse of Drugs issued A review of MDMA ('ecstasy'), its harms and classification under the Misuse of Drugs Act 1971, which recommended that MDMA be re-classified in the UK from a class A drug to a class B drug.

From the Discussion section of the ACMD report on MDMA:

Physical harms: (10.2) Use of MDMA is undoubtedly harmful. High doses may lead to death: by direct toxicity, in situations of hyperthermia/dehydration, excessive water intake, or for other reasons. However, fatalities are relatively low given its widespread use, and are substantially lower than those due to some other Class A drugs, particularly heroin and cocaine. Although it is no substitute for abstinence, the risks can be minimised by following advice such as drinking appropriate amounts of water (see Annex E). (10.3) Some people experience acute medical consequences as a result of MDMA use, which can lead to hospital admission, sometimes with the requirement for intensive care. MDMA poisonings are not currently increasing in number and are less frequent than episodes due to cocaine. (10.4) MDMA appears not to have a high propensity for dependence or withdrawal reactions, although a number of users seek help through treatment services. (10.5) MDMA appears to have little acute or enduring effect on the mental health of the average user, and, unlike amphetamines and cocaine, it is seldom implicated in significant episodes of paranoia. (10.6) There is at the present time little evidence of longer-term harms to the brain in terms of either its structure or its function. However, there is evidence for some small decline in a variety of domains, including verbal memory, even at low cumulative dose. The magnitude of such deficits appears to be small and their clinical relevance is unclear. The evidence shows that MDMA has been misused in the UK for 20 years, but it should be noted that long-term effects of use cannot be ruled out. (10.7) Overall, the ACMD judges that the physical harms of MDMA more closely equate with those of amphetamine than of heroin or cocaine.

Societal harms: (10.8) MDMA use seems to have few societal effects in terms of intoxication-related harms or social disorder. However, the ACMD notes the very small proportion of cases where ‘ecstasy’ use has been implicated in sexual assault. (10.9) Disinhibition and impulsive, violent or risky behaviours are not commonly seen under the influence of MDMA, unlike with cocaine, amphetamines, heroin and alcohol. (10.10) The major issue for law enforcement is ‘ecstasy's’ position, alongside other Class A drugs, as a commodity favoured by organised criminal groups. It is therefore generally associated with a range of secondary harms connected with the trafficking of illegal drugs.


The UK Home Office rejected the recommendation of its independent scientific advisory board to downgrade MDMA to Class B, saying it is not prepared to send a message to young people that it takes ecstasy less seriously.

The government's veto was criticized in scientific publications. Colin Blakemore, Professor of Neuroscience, Oxford, stated in the British Medical Journal, The government's decisions compromise its commitment to evidence based policy. Also in response, an editorial in the New Scientist noted A much larger percentage of people suffer a fatal acute reaction to peanuts than to MDMA.... Sadly, perspective is something that is generally lacking in the long and tortuous debate over illegal drugs.


United States



In the U.S., MDMA was legal and unregulated until 31 May 1985, at which time it was emergency scheduled to DEA Schedule I, for drugs deemed to have no medical uses and a high potential for abuse. During DEA hearings to schedule MDMA, most experts recommended DEA Schedule III prescription status for the drug, due to beneficial usage of MDMA in psychotherapy. The Administrative Law Judge (ALJ) overseeing the hearings, Francis Young, also recommended that MDMA be placed in Schedule III. The DEA however classified MDMA as Schedule I. However, in Grinspoon v. Drug Enforcement Administration, 828 F.2d 881 (1st Cir. 1987), the First Circuit Court of Appeals remanded the scheduling determination for reconsideration by the DEA. MDMA was temporarily removed from Schedule I. Ultimately, in 1988, the DEA re-evaluated its position on remand and subsequently placed MDMA into Schedule I of the Controlled Substances Act.

In 2001, responding to a mandate from the U.S. Congress, the U.S. Sentencing Commission, resulted in an increase in the penalties for MDMA by nearly 3,000%%. The increase in penalties was opposed by the Federation of American Scientists. The increase makes 1 gram of MDMA (four pills at 250 mg per pill's total weight regardless of purity, standard for Federal charges) equivalent to 1 gram of heroin (approximately fifty doses) or 2.2 pounds (1.00 kg) of cannabis for sentencing purposes at the federal level. See also the RAVE Act of 2003.

In a 2011 federal court hearing the American Civil Liberties Union successfully argued that the sentencing guideline for MDMA/ecstasy is based on outdated science, leading to excessive prison sentences.


Netherlands



The Expert Committee on the List (Expertcommissie Lijstensystematiek Opiumwet) of the Netherlands issued a report in June 2011 which discussed the evidence for harm and the legal status of MDMA. From the English-language summary:

As regards MDMA, better known as XTC, the committee concludes that investigations show that damage to the health of the individual in the long term is less serious than was initially assumed. But the extent of the illegal production and involvement of organised crime leads to damage to society, including damage to the image of the Netherlands abroad. This argues in favour of maintaining MDMA on List I.


The Committee noted that research had found the health risks of MDMA were less serious than previously assumed (citing the 2009 UK ACMD report), and so they considered moving MDMA out of the Dutch List I ('hard drugs') to List II ('soft drugs' such as cannabis), but this was not acceptable because the criminal black market would continue to produce all the MDMA. Note, the Committee did not discuss permitting legally regulated production of MDMA for non-medical use because this is not allowed under the UN 1971 Convention on Psychotropic Substances.


Canada



Listed as a Schedule 1 as it is an analogue of amphetamine. The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule 3 to Schedule 1.


World Health Organization



In 1985 the World Health Organization's Expert Committee on Drug Dependence recommended that MDMA be placed in Schedule I of the 1971 Convention on Psychotropic Substances, despite noting:

No data are available concerning its clinical abuse liability, nature and magnitude of associated public health or social problems.


The decision to recommend scheduling of MDMA was not unanimous:

One member, Professor Paul Grof (Chairman), felt that the decision on the recommendation should be deferred awaiting, in particular, the data on the substance's potential therapeutic usefulness and that at this time international control is not warranted.


The 1971 Convention has a provision in Article 7(a) that allows use of Schedule I drugs for scientific and very limited medical purposes. The committee's report stated:

The Expert Committee held extensive discussions concerning therapeutic usefulness of 3,4 Methylenedioxymethamphetamine. While the Expert Committee found the reports intriguing, it felt that the studies lacked the appropriate methodological design necessary to ascertain the reliability of the observations. There was, however, sufficient interest expressed to recommend that investigations be encouraged to follow up these preliminary findings. To that end, the Expert Committee urged countries to use the provisions of article 7 of the Convention on Psychotropic Substances to facilitate research on this interesting substance.


Environmental concerns



Demand for safrole, a substance used in the manufacture of MDMA, is causing rapid and illicit harvesting of the Cinnamomum parthenoxylon tree in Southeast Asia, in particular the Cardamom Mountains in Cambodia. Demand for safrole, mostly for industrial use but also for MDMA production, depletes around 500,000 trees per year in China, Brazil, Cambodia, Vietnam, and Laos. In 2008 alone, Australian and Cambodian authorities blocked and destroyed the export of 33 tons of safrole, capable of producing 245 million ecstasy tablets with a street value of 7.6 billion dollars. Only a small proportion of illicitly harvested safrole is going toward MDMA production, as over 90%% of the global safrole supply (approx 2000 metric tons per year) is used to manufacture pesticides, fragrances, and other chemicals. Sustainable harvesting of safrole is possible from leaves and sticks of certain plants. Safrole is not required for MDMA production, and other precursor chemicals are often used instead.


Cost and distribution



The European Monitoring Centre for Drugs and Drug Addiction notes that, although there are some reports of tablets being sold for as little as €1, most countries in Europe now report typical retail prices in the range of €3 to €9 per tablet. The United Nations Office on Drugs and Crime claimed in its 2008 World Drug Report that typical U.S. retail prices are US$20 to $25 per tablet, or from $3 to $10 per tablet if bought in batches.


Australia



MDMA is expensive in Australia, costing A$20–A$50 per tablet. In terms of purity data for Australian MDMA, the average is around 34%%, ranging from less than 1%% to about 85%%. The majority of tablets contain 70–85 mg of MDMA. Most MDMA enters Australia from the Netherlands, the UK, Asia, and the U.S.


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احبتي ان الحياة علي ظهر هده الارض موقوتة محدوده وستاتي النهايه حتما.
شوفوا هدا المقطع الذي ممكن بسببه ان تترك كل ما لا يرضاه الله عليه

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حتي في بعض الأحيان تظن ان الحيوانات يفكرون في شئ ما ممكن في عجائب الدنيا التي خلق الله سبحانه وتعالى فتسبح لربها.
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انوكنتم تحبون رسول الله صلى الله عليه وسلم فاحيوا سنته غدالك الحب الحقيقي للرسول صلى الله عليه وسلم.
قوله صلى الله عليه وسلم من احيا سنتي فقد احبني ومن احبني كان معي في الجنه.
وقفوا عن المالات الكادبه التي تنشرونها بشبكات النت وو سائل الاعلام.
هيا ندهب الي المساجد كي نصلي في الجماعه....................................كل الاعمال الصالحة التي يحبها الرسول صلى الله عليه وسلم.
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اللهم صلي على محمد وعلى ال محمد كما صليت علي ابراهيم وعلي ال ابراهيم انك حميد مجيد
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