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[top]Introduction to Amphetamine



Amphetamine is a sympathomimetic drug that acts as a powerful central nervous system stimulant. Amphetamine use produces many effects including increased energy, increased alertness, euphoria and decreased appetite. The effects of amphetamine have been linked to mechanisms of action involving numerous neurotransmitters including dopamine, serotonin, norepinephrine and 5-hydroxytryptamine (5-HTP).

Amphetamine is available in several pharmaceutical formulations (Adderall, Dexedrine, Dextrostat, etc) for the treatment of certain medical conditions including ADHD, narcolepsy and chronic fatigue syndrome. Several street forms of amphetamine are also common in parts of the world. Both pharmaceutical and street forms of amphetamine have a very high potential for abuse and carry significant risk of addiction.

Amphetamine is a racemic mixture containing equal parts of its two enantiomers, dextroamphetamine and levoamphetamine. D-amphetamine is considered to be several times more potent than l-amphetamine. The term amphetamine refers to the racemic mixture, while it is preferable to specify when referring to d-amphetamine or l-amphetamine alone.[1]

The term amphetamine is the source of some confusion, as it is often used to refer to a broad category of analogs and derivatives of amphetamine. Although these compounds are related to amphetamine (especially Methamphetamine), they are separate substances.[2][3] This article deals only with the specific drug amphetamine, including its enantiomers.


[top]Using Amphetamine

[top]Ways of administration

[top]Oral


Description: Oral administration of amphetamine is the only route used in the therapeutic setting, but is also very common as a method of recreational use.[4] The effects from an oral dose of amphetamine appear within 15 to 60 minutes, peak within 2 to 3 hours and begin to decline shortly after.[5] Amphetamine preparations with a timed release mechanism usually release half of the drug right away, resulting in the same onset and peak times. The second half of the amphetamine is released about 4 hours later, which delays the decline in effects by about 3 to 4 hours compared to immediate release forms.[6][7]

Method: Oral administration of amphetamine often requires no preparation, making it the easiest option in many cases. Amphetamine powder can be taken orally by parachuting, mixing with a liquid or putting it into capsules. In some areas of the world a white paste form of amphetamine is common, which can be swallowed alone or mixed with liquid to mask the taste. Pharmaceutical amphetamine preparations require no preparation for oral administration since this is their intended route. However, it is common for users to modify extended release forms of amphetamine to receive the full dose at once. This is done by removing the amphetamine-containing beads from the capsule and crushing them to destroy the mechanism that causes the extended release. The most common tool for crushing the beads is a mortar and pestle but other improvised tools can be used, such as a simple plastic bag and hammer.[8][9] The amphetamine is then ingested by parachuting or putting it back into the capsule, resulting in the entire dose being absorbed at once, producing identical effects to any immediate release form.

Notes / Warnings: The oral route of administering amphetamine is generally the safest available method. Many of the common impurities in street amphetamine will be dealt with by the first-pass effect. However, some impurities may still cause ill effects when taken orally. While oral administration of amphetamine is the safest method, it also produces a less intense (though longer lasting) effect. Several factors also affect the pharmacokinetics of an oral amphetamine dose. See the section on pharmacokinetics for a full discussion of these factors. See: Pharmacokinetics

[top]Insufflation


Description: Intranasal administration (or snorting) of amphetamine is not used in the therapeutic setting. However, snorting amphetamine is the second most reported route of administration.[4][10] Insufflation involves inhaling amphetamine into the nose where it is absorbed rapidly through the mucous membrane. This method has not been well studied due to its lack of therapeutic value. Anecdotal evidence and user reports show that snorting amphetamine increases its bioavailability, resulting in a more intense effect. When insufflated, the effects of amphetamine appear within minutes and have a shorter duration of effect.[11]

Method: Insufflation of amphetamine requires that it be in the form of a fine powder. Street forms of amphetamine that are already in powdered form typically require little to no additional preparation before snorting. Amphetamine paste can be dried out, resulting in a solid form that can be snorted.[12] Pharmaceutical preparations of amphetamine can also be snorted, but require varying amounts of preparation first. Instant release tablets are crushed into a fine powder.[13] Extended release amphetamine preparations require that the beads be removed from the capsule and crushed in to a fine powder.[11] This can be done using a mortar and pestle or an improvised tool such as a simple plastic bag and hammer.[8][9] Once the amphetamine tablets or beads have been crushed into a powder, it is either snorted directly or occasionally purified first to remove binders and other ingredients. Some specific brand names of amphetamine are easier to snort due to differences in tablet size, even when comparing within the same dosage. For instance, CorePharma LLC produces amphetamine salt combinations in dosages of both 10mg and 20mg, with both tablets being approximately the same physical size. Meanwhile, a 20mg amphetamine salt combo produced by Barr Pharmaceuticals, Inc. has a smaller physical size compared to both dosages produced by CorePharma.[14] This smaller size results in less material to snort.

Notes / Warnings: Snorting amphetamine is generally safer than injecting it or administering it rectally. However, ill effects can result from impurities, improper preparation or improper technique. Street forms of amphetamine can contain impurities that can have different negative effects, ranging from irritation to significant nasal membrane damage. Pharmaceutical amphetamine preparations typically contain binders, dyes or other ingredients that can cause irritation and/or contribute to an unpleasant “drip”. The extended release versions of amphetamine are often much more difficult to prepare for insufflation, so instant release tablets are usually preferred. While snorting amphetamine produces a more rapid and intense high, this results in a shorter duration of effect and causes a more dramatic comedown.[11]

[top]Injection


Description: Injection of amphetamine is also not used in the therapeutic setting, but in recreational settings, or occasionally during tests with animals. The practice of injecting amphetamine remains somewhat common in some parts of the world mainly due to the intense and almost immediate rush it gives users.[10][15][16] Injected doses of amphetamine are usually administered intravenously or subcutaneously, and are circulated rapidly through the bloodstream. Injecting amphetamine has the highest bioavailability and produces a very rapid and intense effect. When injected, the effects of amphetamine appear almost immediately and are typically short-lived.[17] While injection of amphetamine is the most effective method, it is also the most complicated and dangerous, and thus not recommended.

Method: Keep in mind the dangers of injecting amphetamine, this is a basic overview of the methods and is not meant to be used as a step-by-step guide. Amphetamine powders or pastes are usually the easiest to prepare for injection. Instant release pharmaceutical forms of amphetamine are crushed into a very fine powder.[18] Extended release amphetamine medications are generally not used because the beads are difficult to crush into a fine enough powder and they contain even more undesirable inactive ingredients.[17] Once the amphetamine is in powdered form, an A/B extraction or other cleaning method may be done to remove impurities, binders, dyes and other inactive ingredients. The amphetamine powder is then dissolved in sterile water to create a solution. The amphetamine solution is filtered one or more times using a cigarette filter, coffee filter or similar. The resulting filtered amphetamine solution is then administered to a sterile injection site using a sterile syringe.[17][18][19]

Notes / Warnings: Injection is the most complicated and dangerous method of administering amphetamine. Many variables can cause dose ineffectiveness, serious side effects or death. Aside from the inherent risks of the injection method (disease transmission via used needle, infection, abscesses and other damage due to improper technique, etc) there are significant risks posed by the ingredients of any amphetamine form.[20] Street forms of amphetamine may contain impurities or cutting agents that can cause serious side effects or death. Pharmaceutical amphetamine formulations contain binders, dyes and other inactive ingredients which can cause significant harm.[18] Extended release forms of amphetamine are of particular danger because it is difficult to crush the beads into a fine enough powder to dissolve completely in water.[17] Dosage may also need to be adjusted since injecting amphetamine increases the risk of overdose.[19] One must research exhaustively, be fully informed on harm reduction and know the specifics before even considering attempting to inject amphetamine.

[top]Rectal


Description: Rectal administration (or plugging) of amphetamine is not as common as the other routes and has not been studied or reviewed. Rectal administration involves inserting the amphetamine (usually in a solution with water) into the rectum where it is absorbed. Anecdotal evidence and user reports suggest that amphetamine has good bioavailability when administered rectally. Users report that the effects of rectally administered amphetamine come on more quickly than with oral administration, but not as quickly as with insufflation or injection. Plugging amphetamine seems to produce effects that are more intense than those given by oral administration, but not approaching the intensity of effects produced by injection.[21][22] When compared to insufflation, the intensity of effects from a rectally administered dose of amphetamine varies from user to user, but are often comparable. Rectal administration of amphetamine also seems to have a shorter duration of effects than the oral route.[22]

Method: Some reports suggest that amphetamine powder or tablets can be inserted directly if dampened with water.[22] However this is not common as it may result in significant irritation. A more common method involves mixing the amphetamine powder or crushed pharmaceutical amphetamine with water. The resulting solution is then administered rectally, usually with a syringe.[22]

Notes / Warnings: The safety of administering amphetamine rectally has not been established. However, the rectal administration method is generally safer than that of injection. Administering amphetamine rectally can cause varying amounts of irritation depending on the methods used, the presence of inactive ingredients and personal factors. The presence of impurities, binders, dyes and other inactive ingredients can contribute significantly to discomfort and/or irritation. Very little data exists examining the results of rectal amphetamine administration.

[top]Effects of Amphetamine

[top]Main Effects


Most Common: The following is a list of the most documented effects of amphetamine. These are the effects for which amphetamine is most well known and are observable in the majority of cases.[23][24]
  • Increased energy
  • Euphoria
  • Decreased appetite
  • Increased concentration
  • Increased motivation


Rare: There is some evidence in medical literature showing that amphetamine occasionally produces atypical or even opposite effects in some users. The reasons for these rare cases have not been identified. While uncommon and poorly understood, these effects include drowsiness and lowered electrical brain activity.[25]

[top]Side Effects


Most Common: While amphetamine use can have many side effects, some are far more prevalent than others. According to side effect profiles from medical literature and clinical trials, the most common side effects of amphetamine use are as follows.[27,28,29,30]
  • Decreased Appetite
  • Dry Mouth
  • Headache
  • Weight Loss
  • Anxiety / Nervousness


Prevalence of Most Common Side Effects in Clinical Trials
SymptomGroup 1[26]Group 2[27]Group 3[28]Group 4[29]Avg % Affected
 
Decreased Appetite
Insomnia
Dry Mouth
Headache
Weight Loss
Anxiety / Nervousness
Somewhat Common: Amphetamine use also produces several side effects that are less common than the first category. These side effects range in frequency of occurrence, but appear often enough to be statistically significant.[27,28,29,30]
  • Increased heart rate / blood pressure
  • Increased body temperature / sweating
  • Increased breathing rate
  • Agitation / irritability
  • Abdominal pain
  • Emotional lability / mood swings
  • Depression
  • Nausea
  • Tachycardia
  • Diarrhea
  • Dizziness
  • Twitching
  • Abnormal thought patterns
  • Pupil dilation
  • Palpitations
  • Constipation
  • Impotence / sexual side effects
  • Increased aggressiveness
  • Increase in risk taking behavior
  • Rash
  • Confusion


Rare or Resulting from Heavy / Chronic Doses: Some of the side effects that amphetamine can cause do not often appear under normal circumstances. Usually, heavy and/or chronic doses of amphetamine are required to produce these side effects.[27,28,29,30]
  • Acne, sores or skin conditions
  • Exasperation or worsening of symptoms of Tourette Syndrome, Schizophrenia or other conditions
  • Panic attacks
  • Convulsions
  • Psychotic episodes


[top]Combinations with Amphetamine


Combining amphetamine with other substances can affect one or both drugs in different ways. Potentiation, enhancing of effects, changes in side effects or other synergistic effects can result from combining amphetamine with other drugs. Usage statistics have shown that a high percentage of amphetamine users are poly drug users, which increases the likelihood of amphetamine being combined with other substances.[30] While this practice is common, care must be taken when combining amphetamine with other drugs. There is often a fine line between a safe combination and a dangerous interaction. This can often be hard to determine due to the presence of limited or nonexistent clinical and scientific data examining specific combinations. One should review all known dangerous interactions and information before attempting to combine amphetamine with another drug. See: Dangerous Interactions.

[top]Alcohol


Can allow one to engage in extended binge drinking, which poses additional dangers. Can increase likelihood of aggressive and/or irresponsible behavior. Increases heart rate, and there have been reports of myocardial infarction when mixing alcohol and amphetamines. Not good for liver and kidneys. Terrible hangover.

[top]Nicotine

[top]Cannabis

[top]Opium and Opium-Related Alkaloids

[top]Benzodiazepines and Other Downers

[top]Other Uses for Amphetamine



[top]Pharmacology of Amphetamine


Amphetamine occurs as a racemic mixture of d-amphetamine and l-amphetamine. D-amphetamine primarily acts to release dopamine into the synaptic cleft while it's isomer l-amphetamine acts primarily to release norepinephrine. Amphetamine causes these increases in synaptic monoamines by binding to and inhibiting their reuptake (eg the Dopamine Transporter, DAT). The manner in which amphetamine inhibits DAT differs from cocaine. While cocaine blocks DAT, amphetamine phosphorylates DAT causing it to be internalized by the neuron. Additionally, at the same time amphetamine is also causing dopamine storage vesicles (Vesicular Monoamine Transporters, VMATs) to release more monoamines into the synaptic cleft.


[top]Dangers of Amphetamine

[top]Short Term Use


Amphetamines can be extremely dangerous or fatal from the first use. Users may die from burst blood vessels in the brain, heart failure, or super-elevated body temperature.

Common short-term effects include:
  • Dry mouth
  • Headache
  • Dilated pupils
  • Insomnia
  • Dry, itchy skin
  • Acne, sores
  • Dizziness and blurry vision
  • Loss of coordination
  • Uncontrollable movements (twitching, jerking, tremors, etc.)
  • Fever, flushing, and sweating
  • Diarrhea or constipation
  • Numbness
  • Impaired speech
  • Increased heart rate
  • Rapid breathing rate
  • Elevated blood pressure
  • Rise in body temperature
  • Convulsions
  • Irregular heartbeat

[top]Overdose


Amphetamine overdose is fairly common, which is probably due to abusers’ ever-increasing need for more and more of the drug (tolerance.) Abusers try to overcome their tolerance by escalating their use, they overdo it, and they overdose.

Amphetamine overdose is often fatal. Symptoms include:
  • Chills, fever, and sweating
  • Muscle spasms, including severely exaggerated arching of the back
  • Convulsions
  • Lack of urine output
  • Difficulty breathing
  • Dilated pupils and blurred vision
  • Blue lips and fingernails
  • Nausea and/or vomiting
  • Elevated blood pressure, followed by a dramatic drop in blood pressure
  • Irregular heartbeat
  • Chest pain
  • Nervousness, irritability
  • Restlessness
  • Aggressive behavior
  • Coma

[top]Long Term Use


Amphetamines cause a wide variety of potentially fatal damage to users’ mental and physical health. One of the most troubling effects of amphetamine abuse is the addiction itself, which can be life-altering. Withdrawal causes painful side effects, as well.
  • Addiction
    • Amphetamine psychosis (see below)
    • Craving
    • Tolerance
    • Dependence


  • Withdrawal
    • Craving
    • Exhaustion
    • Depression
    • Mental confusion
    • Restlessness and insomnia
    • Deep and disturbed sleep lasting up to 48 hours
    • Extreme hunger
    • Psychosis
    • Intense anxiety
    • Other serious, long-term damage caused by amphetamine abuse includes:


  • Gastrointestinal/Nutritional Damage
    • Malnutrition
    • Ulcers
    • Unwanted weight loss


  • Heart Disease
    • Rapid heart rate
    • Dangerously high blood pressure
    • Cardiomyopathy (enlarged and/or weakened heart)
    • Heart attack


  • Neurological Damage
    • Permanent brain damage
    • Disturbed thought processes
    • Speech difficulties
    • Confusion
    • Memory loss

    Psychological Damage
    • Hallucinations
    • Deep depression
    • Hypochondria (the false belief that one is physically ill)
    • Delusions of power or fame
    • Antisocial behavior
    • Stereotypic behaviors (odd repetitive movements or habits)
    • Psychosis: paranoia, bizarre and violent behavior


  • Danger to Newborns of Women Who Use During Pregnancy
    • Addiction and withdrawal
    • Cardiac defects
    • Cleft palate
    • Other physical abnormalities
    • Developmental delays
    • Neurological damage not detectable at birth

    Other Damage
    • Liver damage
    • Impotence



[top]Dangerous Interactions


Do not take amphetamine if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), tranylcypromine (Parnate), or phenelzine (Nardil) in the last 14 days.

Adderall can interact with a variety of other prescription medications, causing a variety of issues. Drugs used to treat high blood pressure that create acidity in the stomach, such as guanethidine and reserpine, that can cause problems with the absorption of Adderall, meaning that higher dosages may be necessary that in turn can lead to an increase in other risks associated with Adderall.

Tricyclic antidepressants, such as Elavil and Adapin, can cause an increase of amphetamine accumulation from Adderall in the brain, that can lead to heart problems and impairment of cognitive brain functions.

MAO inhibitors used to treat Parkinson's Disease, social anxiety and depression can have dangerous interactions with Adderall, including dangerous increases in blood pressure and a possibility of blood toxicity that can result in death.





[top]Chemistry of Amphetamine

[top]Dosage Forms of Amphetamine

[top]Synthesis of Amphetamine



[top]Legal status of Amphetamine

A Schedule II drug is classified as one that has a high potential for abuse, has a currently-accepted medical use and is used under severe restrictions, and has a high possibility of severe psychological and physiological dependence.

[top]United Nations

Under the Convention on Psychotropic Substances Treaty of 1971, amphetamines are classified as a Schedule II drug

[top]USA

In the United States, amphetamine and methamphetamine are Schedule II drugs, classified as CNS (central nervous system) stimulants.

In Canada, possession of amphetamines is a criminal offence under Schedule III of the Controlled Drugs and Substances Act, with a maximum penalty for repeat offenders of fines of up to $2,000, imprisonment for up to one year, or both.

[top]EU

In the United Kingdom, amphetamines are regarded as Class B drugs. The maximum penalty for unauthorized possession is five years in prison and an unlimited fine. The maximum penalty for illegal supply is 14 years in prison and an unlimited fine.

In the Netherlands, amphetamine and methamphetamine are List I drugs of the Opium Law, but the dextro isomer of amphetamine is indicated for ADD/ADHD and narcolepsy and available for prescription as 5 and 10 mg generic tablets, and 5 and 10 mg gel capsules.




[top]History of Amphetamine

Amphetamine was first synthesized in 1887 by the Romanian chemist Lazăr Edeleanu in Berlin. He named the compound phenylisopropylamine. It was one of a series of compounds related to the plant derivative ephedrine, which had been isolated from Ma-Huang that same year by Nagayoshi Nagai. No pharmacological use was found for amphetamine until 1927, when pioneer psychopharmacologist Gordon Alles resynthesized and tested it on himself, in search of an artificial replacement for ephedrine. From 1933 or 1934 Smith, Kline and French began selling the volatile base form of the drug as an inhaler under the trade name Benzedrine, useful as a decongestant but readily usable for other purposes.

One of the first attempts at using amphetamine as a scientific study was done by M. H. Nathanson, a Los Angeles physician, in 1935. He studied the subjective effects of amphetamine in 55 hospital workers who were each given 20 mg of Benzedrine. The two most commonly reported drug effects were "a sense of well being and a feeling of exhilaration" and "lessened fatigue in reaction to work".
During World War II amphetamine was extensively used to combat fatigue and increase alertness in soldiers. After decades of reported abuse, the FDA banned Benzedrine inhalers, and limited amphetamine to prescription use in 1965, but non-medical use remained common. Amphetamine became a schedule II drug in the USA under the Controlled Substances Act in 1971.
The related compound methamphetamine, in its crystallized form, was first synthesized from ephedrine in Japan in 1920 by chemist Akira Ogata, via reduction of ephedrine using red phosphorus and iodine. The pharmaceutical Pervitin was a tablet of 3 mg methamphetamine that was available in Germany from 1938 and widely used in the Wehrmacht, but by mid-1941 it became a controlled substance, partly because of the amount of time needed for a soldier to rest and recover after use and partly because of abuse. For the rest of the war, military doctors continued to issue the drug, but less frequently and with increasing discrimination.
In 1997 and 1998, researchers at Texas A&M University claimed to have found amphetamine and methamphetamine in the foliage of two Acacia species native to Texas, A. berlandieri and A. rigidula. Previously, both of these compounds had been thought to be human inventions. These findings have never been duplicated, and the analyses are believed by many biochemists to be the result of experimental error, and as such the validity of the report has come into question. Alexander Shulgin, one of the most experienced biochemical investigators and the discoverer of many new psychotropic substances, has tried to contact the Texas A&M researchers and verify their findings. The authors of the paper have not responded; natural amphetamine remains an unconfirmed discovery.


Popularity of Amphetamine over time:



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