Amphetamine – Uses and Dose

Background

Amphetamine, a compound discovered over 100 years ago, is one of the more restricted controlled drugs. It was previously used for a large variety of conditions and this changed until this point where its use is highly restricted. Amphetamine, with the chemical formula alpha-methylphenethylamine, was discovered in 1910 and first synthesized by 1927. After being proven to reduce drug-induced anesthesia and produce arousal and insomnia, amphetamine racemic mix was registered by Smith, Kline and French in 1935. Amphetamine structure presents one chiral center and it exists in the form of dextro- and levo-isomers. The first product of Smith, Kline and French was approved by the FDA on 1976.

During World War II, amphetamine was used to promote wakefulness in the soldiers. This use derived into a large overproduction of amphetamine and all the surplus after the war finalized ended up in the black market, producing the initiation of the illicit abuse.

Types of amphetamine

The appearance of amphetamines varies from powder and tablet to crystals and capsules. The most common amphetamine in Australia is methamphetamine, which comes in three forms:

• Ice (crystal methamphetamine) – is a crystal or crystalline powder, and is a stronger form of methamphetamine. It is also known as ‘crystal meth’, ‘shabu’ shard or ‘glass’
• Speed – usually comes in the form of a powder
• Base – is an oily, sticky or waxy paste.

Amphetamines can be injected, snorted, smoked or swallowed.

It is illegal to make or sell amphetamines. It is also illegal to possess or use amphetamines, unless they have been prescribed by a doctor for medical reasons.

Illegally produced amphetamines can be a mix of drugs, binding agents, caffeine, new psychoactive substances and sugar.

Properties and Characteristics of Amphetamine

Drug class	Stimulant drugs
Brand Names	Adderall, Adzenys, Dyanavel, Evekeo, Mydayis
Synonyms	Alpha-Methylbenzeneethaneamine, Amfetamina, Amfetamine Amfetaminum, Amphetamine, beta-Aminopropylbenzene, beta-Phenylisopropylamin, Desoxynorephedrine, rac-amphetamine
Molecular Formula	C9H13N
Molecular Weight	135.21 g/mol
IUPAC Names	1-phenylpropan-2-amine
Structural formula of main components
Pure active ingredient	Amphetamine
Appearance	White, odourless, bitter-tasting crystalline powders
Melting point	-98 ºC
Solubility	1.74 mg/mL
Excretion	Elimination of amphetamine is mainly via the urine
Available as	Capsules, Tablet, and Suspension
Storage	Recommended storage temperature is -20 °C
Prescription	Doctors prescription is required

Medical uses of Amphetamine

Amphetamine activates receptors in the brain and increases the activity of a number of neurotransmitters, especially norepinephrine and dopamine.

Dopamine is associated with pleasure, movement, and attention.

Amphetamine has been trialed for a wide variety of conditions. Now, it is mainly used to treat ADHD, and, rarely, depression. In the past, it has been used to treat narcolepsy and to help with weight loss, but this is less common now.

Attention deficit hyperactivity disorder

ADHD is characterized by hyperactivity, irritability, mood instability, attention difficulties, lack of organization, and impulsive behaviors.

It often appears in children, but it can continue into adulthood.

Amphetamines reverse some of these symptoms and have been shown to improve brain development and nerve growth in children with ADHD.

Long-term treatment with amphetamine-based medication in children appears to prevent unwanted changes in brain function and structure.

Scientists carrying out a review of 20 studies concluded that stimulants are probably helpful for people with ADHD.

They found that the brain structures of people who took stimulants for ADHD were more likely to resemble the brain structures of people without the condition than to resemble those with ADHD who did not use the drugs.

A review published in Cochrane in 2011 suggested that adults with ADHD might benefit from short-term use of amphetamines, but that they were unlikely to persist with the treatment because of adverse effects. Those who use mixed amphetamine salts, however, were more likely to continue with the treatment.

Narcolepsy

A person with narcolepsy will experience excessive daytime sleepiness and irresistible sleep episodes, called “sleep attacks.”

In a person with this condition, strong emotions can trigger a sudden loss of muscle tone, or cataplexy, which causes a person to collapse and possibly fall down. It also involves frequent and unexpected bouts of sleep.

Amphetamines and amphetamine derivatives have been used in the past to treat narcolepsy.

Due to concerns over their side effects, however, amphetamines are increasingly being replaced by modafinil, a medication that promotes wakefulness.

Obesity

Under the name Benzedrine, amphetamines were first used to treat obesity in the 1930s, due to their appetite-suppressing capabilities.

Fears of the drug’s side effects and its potential for addiction and abuse caused them to fall out of favor for this purpose. In the 1950s, reports of malnutrition, psychosis, and depression on withdrawal caused doctors to stop prescribing amphetamines for weight loss.

Currently, medical professionals do not recommend using amphetamines and their derivatives to help reduce obesity.

However, in 2015, after carrying out a small study, researchers suggested that dexamphetamine might be a safe and effective way of boosting people’s motivation for lifestyle changes that can lead to weight loss.

They proposed a 6-month use of the drug to help people who have not responded to other treatment to improve their diet and increase exercise levels. This, they say, could help curb obesity and related complications, such as diabetes and cardiovascular disease.

Depression

From the 1930s, amphetamine was used to treat affective disorders, obsessive-compulsive disorder (OCD), and schizophrenia.

However, in the 1950s and 1960s, amid growing concern about its adverse effects, it was replaced by newly available antidepressants.

In rare cases, amphetamines are used alongside standard antidepressants to treat some types of depression that do not respond to other treatments, especially in people who also experience fatigue and apathy.

Side Effects of Amphetamine

Amphetamine can produce many side effects, ranging from mild to severe.

Physical side effects include:

• Low or high blood pressure
• Raynaud’s phenomenon, where there is reduced blood flow to the extremities
• Erectile dysfunction, and especially frequent or persistent erections
• Rapid heart rate
• Abdominal pain
• Loss of appetite, nausea, and weight loss
• Acne, rash, hives
• Blurred vision
• Dry mouth
• Teeth grinding
• Nosebleed
• Profuse sweating
• Nasal congestion
• Increased likelihood of seizures for susceptible individuals
• Tics
• Faster, deeper breaths, especially in those with other lung conditions
• Difficulty urinating

There may also be psychological effects.

These include:

• Increased alertness and focus
• Apprehension, anxiety, irritability, and restlessness
• Mood swings
• Insomnia
• Changes in libido
• Grandiosity, or an exaggerated sense of one’s own importance
• Obsessive behaviors

In rare cases, psychosis may occur

People who follow the prescribed, therapeutic dose are unlikely to experience severe adverse effects.

There have been fears that long-term use of amphetamines for ADHD could affect brain development, prevent physical growth, and increase the risk of drug abuse later in life. However, animal studies have suggested that this is unlikely.

Mechanism of Action

It is important to consider that amphetamine has a very similar structure to the catecholamine neurotransmitters mainly on the presence of a long planar conformation, the presence of an aromatic ring and nitrogen in the aryl side chain. Amphetamine, as well as other catecholamines, is taken into presynaptic nerve terminals by the association with two sodium ions and one chloride ion. The complex of the amphetamine with the ions is actively transported by monoamine reuptake transporters. As amphetamine acts competitively with the endogenous monoamines, the greater the number of amphetamines the more internalized amphetamine will be found.

Once inside the presynaptic terminal, amphetamine displaces other monoamines to be stored by VMAT2 which produces the pumping of the neurotransmitters into the synapse by a process called retro-transport. This process of release of neurotransmitters is approximately fourfold more potent in the d-isomer for the release of dopamine.

The mechanism of action of amphetamine is complemented by the inhibition of the reuptake and of monoamine oxidase which acts synergistically to produce a significant increase the monoamine concentration. This activity is not done as an inhibitor per se but more as a competitive substrate and thus, amphetamine is known to be a weak dopamine reuptake inhibitor, moderate noradrenaline reuptake inhibitor and very weak serotonin reuptake inhibitor. From this specific action, the l-isomer is known to be significantly less potent.

Lastly, amphetamine is known to be an inhibitor of the mitochondrial-bound enzyme MAO which is the catalytic enzyme in charge of degrading all the excess of neurotransmitters. This mechanism of action is often overpassed as amphetamine is a weak MAO inhibitor but this mechanism cannot be dismissed.

Drug Interactions with Amphetamine

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (such as prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor’s approval.

Taking MAO inhibitors with this medication may cause a serious (possibly fatal) drug interaction. Avoid taking MAO inhibitors (isocarboxazid, linezolid, metaxalone, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, safinamide, selegiline, tranylcypromine) during treatment with this medication. Most MAO inhibitors should also not be taken for two weeks before treatment with this medication. Ask your doctor when to start or stop taking this medication.

Some products have ingredients that could raise your heart rate or blood pressure. Tell your pharmacist what products you are using, and ask how to use them safely (especially cough-and-cold products or diet aids).

The risk of serotonin syndrome/toxicity increases if you are also taking other drugs that increase serotonin. Examples include street drugs such as MDMA/ “ecstasy,” St. John’s wort, certain antidepressants (including SSRIs such as fluoxetine/paroxetine, SNRIs such as duloxetine/venlafaxine), among others. The risk of serotonin syndrome/toxicity may be more likely when you start or increase the dose of these drugs.

Amphetamine is very similar to dextroamphetamine or lisdexamfetamine. Do not use medications containing dextroamphetamine or lisdexamfetamine while using amphetamine.

This medication may interfere with certain medical/lab tests (such as blood and urine steroid levels, brain scan for Parkinson’s disease), possibly causing false test results. Make sure lab personnel and all your doctors know you use this drug.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor’s orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

For ADHD:

For oral dosage form (extended-release oral disintegrating tablets):

• Adzenys XR-ODT®:
  • Adults—12.5 milligrams (mg) once a day, in the morning.
  • Children 13 to 17 years of age and older—At first, 6.3 mg once a day, in the morning. Your doctor may increase your dose as needed. However, the dose is usually not more than 12.5 mg per day.
  • Children 6 to 12 years of age—At first, 6.3 mg once a day, in the morning. Your doctor may increase your dose as needed. However, the dose is usually not more than 18.8 mg per day.
  • Children younger than 6 years of age—Use and dose must be determined by your doctor.
• Evekeo ODT®:
  • Children 6 to 17 years of age—At first, 5 milligrams (mg) 1 or 2 times a day, in the morning. You may add another dose after 4 to 6 hours. Your doctor may increase your dose as needed. However, the dose is usually not more than 40 mg per day.
  • Children younger than 6 years of age—Use and dose must be determined by your doctor.

For oral dosage form (extended-release tablets):

• Adults and children 6 years of age and older—At first, 2.5 or 5 milligrams (mg) once a day, in the morning. Your doctor may increase your dose as needed. However, the dose is usually not more than 20 mg per day.
• Children younger than 6 years of age—Use and dose must be determined by your doctor.

For oral dosage form (extended-release suspension):

• Adzenys ER™:
  • Adults—12.5 milligrams (mg) (10 mL) once a day, in the morning.
  • Children 13 to 17 years of age and older—At first, 6.3 mg (5 mL) once a day, in the morning. Your doctor may increase your dose as needed. However, the dose is usually not more than 12.5 mg (10 mL) per day.
  • Children 6 to 12 years of age—At first, 6.3 mg (5 mL) once a day, in the morning. Your doctor may increase your dose as needed. However, the dose is usually not more than 18.8 mg (15 mL) per day.
  • Children younger than 6 years of age—Use and dose must be determined by your doctor.
• Dyanavel® XR:
  • Adults and children 6 years of age and older—At first, 2.5 or 5 milligrams (mg) once a day, in the morning. Your doctor may increase your dose as needed. However, the dose is usually not more than 20 mg per day.
  • Children younger than 6 years of age—Use and dose must be determined by your doctor.

For oral dosage form (tablets):

• Adults and children 6 years of age and older—At first, 5 milligrams (mg) 1 or 2 times a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 40 mg per day.
• Children 3 to 5 years of age—At first, 2.5 mg once a day. Your doctor may increase your dose as needed.
• Children younger than 3 years of age—Use is not recommended.

For narcolepsy:

For oral dosage form (tablets):

• Adults and children 12 years of age and older—At first, 10 milligrams (mg) once a day, in the morning. Your doctor may increase your dose as needed. However, the dose is usually not more than 60 mg per day.
• Children 6 to 11 years of age—At first, 5 mg once a day, in the morning. Your doctor may increase your dose as needed.
• Children younger than 6 years of age—Use and dose must be determined by your doctor.

For weight loss:

For oral dosage form (tablets):

• Adults and children 12 years of age and older—5 to 10 milligrams (mg) per day, taken 30 to 60 minutes before each meal. Your doctor may increase your dose as needed. However, the dose is usually not more than 30 mg per day.
• Children younger than 12 years of age—Use is not recommended.

Overdose

If you take a large amount or have a strong batch, you could overdose.

Call an ambulance straight away by dialing your emergency number if you or someone else has any of the following symptoms:

• Racing heartbeat
• Fits
• Passing out or breathing difficulties
• Chills or fever
• No urine output
• Arching of the back/convulsions
• Stroke, heart attack and death.

Amphetamine Warnings or Precautions

This drug comes with several warnings.

Allergy warning

This drug can cause an allergic reaction. Symptoms may include:

• Hives
• Trouble breathing
• Swelling of your throat and tongue

If you develop these symptoms, call 911 or go to the nearest emergency room.

Don’t take this drug again if you’ve ever had an allergic reaction to it. Taking it again could be fatal (cause death).

Warnings for people with certain health conditions

For people with heart problems: People with serious heart problems may be at risk for sudden death when taking usual doses of this drug. They shouldn’t take this drug.

This drug may increase blood pressure and heart rate. If you have high blood pressure, heart failure, a history of recent heart attack, or an irregular or abnormal heart beat, you and your doctor should discuss if this drug is safe for you. If you decide to take it, use this drug with extreme caution.

For people with psychiatric disorders: If you or your child already has a psychotic disorder and take this drug, symptoms of behavior problems and thought disorders may get worse.

If you or your child already has bipolar disorder, there’s an increased risk of having a mixed or manic episode when taking this drug.

For people with anxiety or agitation: If you or your child tends to be very anxious, tense, or agitated, don’t use this drug. It can worsen these symptoms.

For people with a history of drug abuse: If you or your child has a history of abuse, don’t use this drug. It can be highly addictive.

For people with seizures: If you or your child has a history of seizures, don’t use this drug. It may increase the risk of having a seizure.

For people with circulation problems: These problems include peripheral vasculopathy and Raynaud’s phenomenon. Amphetamine may damage tissue in your or your child’s fingers and toes. This may cause a feeling of numbness, pain, or cold. Fingers and toes may also change colors from pale, to blue, to red. You and your doctor should monitor your fingers and toes for any of these symptoms. If things worsen, your doctor may decide to decrease the dosage, stop the medication, or refer you to a specialist.

For people with hyperthyroidism: If you or your child has been diagnosed with overactive thyroid (hyperthyroidism), don’t take this drug. It can make hyperthyroidism worse and cause symptoms such as an increased or abnormal heartbeat.

Warnings for other groups

For pregnant women: This drug is a category C pregnancy drug. That means two things:

1. Research in animals has shown adverse effects to the fetus when the mother takes the drug.
2. There haven’t been enough studies done in humans to be certain how the drug might affect the fetus.

Some infants born to mothers who are dependent on amphetamine during pregnancy have shown an increased risk of being born premature, having a low birth weight, or showing symptoms of withdrawal.

Talk to your doctor if you’re pregnant or planning to become pregnant. This drug should be used during pregnancy only if the potential benefit justifies the potential risk.

For women who are breastfeeding: This drug may pass into breast milk and can cause side effects in a child who is breastfed. Tell your doctor if you’re breastfeeding. You may need to decide whether to stop breastfeeding or stop taking this drug. You should not breastfeed while taking this drug.

For children: This drug is safe and effective for children ages 3 to 17 years when used for attention deficit hyperactivity disorder (ADHD). Long-term safety and effectiveness of this drug in children are not well-established.