Amphetamine mixed salts (medication)
|amphetamine aspartate||(25%) psychostimulant|
|amphetamine sulfate||(25%) psychostimulant|
|dextroamphetamine saccharate||(25%) psychostimulant|
|dextroamphetamine sulfate||(25%) psychostimulant|
|Licence data||US Daily Med:|
|Pregnancy cat.||C (US)|
|Legal status||Schedule I (CA) Schedule II (US)|
|Routes||Oral, insufflation, rectal, sublingual|
|ATC code||N06 N06|
| (what is this?)
Amphetamine mixed salts (also known as amphetamine and dextroamphetamine mixed salts, amphetamine salt combo, or simply amphetamine salts, and sold under the brand name Adderall) is a pharmaceutical drug used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The active ingredient contained in this medication is a mixture of multiple salts of the stimulant amphetamine. There is a single commercial formulation only as of 2013, which contains a 3:1 ratio of dextroamphetamine (the dextrorotary or "right-handed" enantiomer) to levoamphetamine (the levorotary or "left-handed" enantiomer).[note 1] Amphetamine mixed salts are available in immediate release and extended release formulations.
- 1 Uses
- 2 Side effects
- 3 Overdose
- 4 Contraindications, interactions, and precautions
- 5 Mechanism of action
- 6 History
- 7 Commercial formulations
- 8 Legal status
- 9 Notes
- 10 References
Amphetamine mixed salt is generally used for the treatment of ADHD and narcolepsy, the two conditions for which the United States Food and Drug Administration has approved its use. However, it is sometimes prescribed off-label for other conditions such as depression. It has been used to treat obesity, but the American Society of Health-System Pharmacists does not recommend this use. Nearly 14 million monthly prescriptions for the condition were written for Americans ages 20 to 39 in 2011, two and a half times the 5.6 million just four years before, according to the data company I.M.S. Health.
Attention deficit hyperactivity disorder
The comparative effectiveness of treatment options for children with ADHD, including different amphetamine medications, has been studied by the US Agency for Health Care Research and Quality, and summarized for parents. Amphetamines may improve ADHD symptoms in children over the age of six, but there is not enough evidence to be sure. Use for younger children and use for longer than a year in particular requires further study.
Amphetamine mixed salts have also been shown to reduce ADHD in adults, but research is limited. According to Millchap et al., "a multicenter, placebo-controlled trial of amphetamine treatment for ADHD in Sweden found significant improvements in attention, hyperactivity, and disruptive behaviors and a mean change in IQ of +4.5 after more than 9 months of amphetamine [use];" however, the authors note that the population in the study had a remarkably high incidence of comorbid disorders associated with ADHD. Consequently, they asserted that other long-term trials of stimulants in ADHD with less comorbidity would be expected to show greater functional improvements and fewer side effects.
Dosing and administration
Amphetamine mixed salts is available as immediate release form or extended-release form. The extended release capsule is generally used in the morning. Generic forms are available in some doses. The extended release formulation available under the brand Adderall XR is designed to provide therapeutic effect and plasma concentrations identical to taking two doses 4 hours apart.
Therapeutic doses of psychostimulants, including amphetamine, improve performance on working memory tests both in normal functioning individuals and those with ADHD. Moreover, these stimulants also increase arousal and, within the nucleus accumbens, improve task saliency. Thus, stimulants improve performance on effortful and tedious tasks as well. Consequently, amphetamine is used by some college and high-school students as a study and test-taking aid. Based upon studies of self-reported illicit stimulant use among college students, performance-enhancing use, as opposed to abuse as a recreational drug, is the primary reason that students use stimulants. In contrast, at doses much higher than those medically prescribed, stimulants can interfere with working memory and cognitive control.
Amphetamine is also used by some professional, collegiate and high school athletes for its strong stimulant effects. However, in competitive sports, this form of use is generally prohibited by anti-doping regulations. At moderate therapeutic doses, amphetamine has been shown to increase physical strength, acceleration, stamina, and endurance, while reducing reaction time. Like methylphenidate and bupropion, amphetamine increases stamina and endurance in humans primarily through reuptake inhibition and effluxion of dopamine in the central nervous system. Similar to cognition enhancement, very high amphetamine doses can induce side effects that impair athletic performance, such as rhabdomyolysis and hyperthermia.
Amphetamine is considered to have a high potential for misuse and a high liability for dependence and listed as Schedule II in the US, Schedule II in the UN Convention of Psychotropic Substances and Schedule I in Canada (CSA). Amphetamine mixed salts is a drug of abuse. Amphetamine salts can be crushed and snorted, or dissolved in water and injected. Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.
The side effects of amphetamine mixed salts are many and varied, but the amount of the drug consumed is the primary factor in determining the likelihood and severity of side effects. The therapeutic use of amphetamine is currently approved by the United States Food and Drug Administration (USFDA) for long-term pharmaceutical use. Recreational use of amphetamine mixed salts generally involves far larger doses and is therefore significantly more dangerous than therapeutic use, and involves a much greater risk of serious side effects.
At normal therapeutic doses, the physical side effects of amphetamine mixed salts vary widely by age and among individuals; these side effects can include abdominal pain, acne, arrhythmias, blurred vision, bruxism, constipation or diarrhea, diaphoresis, dry skin, dry mouth, erectile dysfunction, fever, headache, hypertension or hypotension from a vasovagal response, indigestion, insomnia, loss of appetite, nausea, pallor, palpitations, Raynaud's phenomenon (secondary), reduced seizure threshold, tachycardia, tachypnea, tics, vomiting, and weight loss. Dangerous physical side effects are quite rare in typical pharmaceutical doses.
Amphetamine stimulates the medullary respiratory centers, which increases the rate of respiration and produces deeper breaths. In a normal individual at therapeutic doses, amphetamine does not noticeably increase the rate of respiration or produce deeper breaths, but when respiration is already compromised, they may stimulate respiration. Amphetamine also induces contraction in the urinary bladder sphincter, which can result in difficulty urinating; however, this effect also makes amphetamine useful in treating enuresis and incontinence. In contrast, the effects of amphetamine on the gastrointestinal tract are unpredictable. Amphetamine may reduce gastrointestinal motility if enteric activity is high, or increase motility if the smooth muscle of the tract are relaxed. Amphetamine also has a slight analgesic effect and can further enhance the analgesia of opiates.
Recent studies by the USFDA indicate that, in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, myocardial infarction, and stroke) and the medical use of amphetamine pharmaceuticals or other ADHD stimulants.
Common psychological effects of therapeutic doses can include alertness, apprehension, concentration, decreased sense of fatigue, mood swings (elevated mood or elation and euphoria followed by mild dysphoria), increased initiative, insomnia or wakefulness, self-confidence, and sociability. Less common or rare psychological effects that depend on the user's personality and current mental state include anxiety, change in libido, grandiosity, irritability, repetitive or obsessive behaviors, and restlessness. When heavily abused, amphetamine psychosis can occur. Although very rare, this psychosis can also occur at therapeutic doses during long-term therapy as a side effect. According to the USFDA, "there is no systematic evidence that stimulants cause aggressive behavior or hostility."
An amphetamine overdose is rarely fatal with appropriate care, but can lead to a number of different symptoms. A moderate overdose of amphetamine mixed salts may induce symptoms including: arrhythmia, confusion, dysuria, hypertension or hypotension, hyperthermia, hyperreflexia, myalgia, severe agitation, tachypnea, tremor, urinary hesitancy, and urinary retention. An extremely large overdose may produce symptoms such as adrenergic storm, amphetamine psychosis, anuria, cardiogenic shock, cerebral hemorrhage, circulatory collapse, hyperpyrexia, pulmonary hypertension, renal failure, rhabdomyolysis, serotonin syndrome, and stereotypy.[note 2] Fatal amphetamine poisoning usually also involves convulsions and coma.
Dependence, addiction and withdrawal
While addiction is a serious risk with heavy recreational amphetamine use, it is unlikely to arise from typical medical use. Tolerance is developed rapidly in amphetamine abuse; therefore, periods of extended use require increasing amounts of the drug in order to achieve the same effect. According to a Cochrane Collaboration review on withdrawal in highly dependent amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose." This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for 3–4 weeks with a marked "crash" phase occurring during the first week. Amphetamine withdrawal symptoms can include fatigue, dysphoric mood, increased appetite, vivid or lucid dreams, hypersomnia or insomnia, increased movement or decreased movement, anxiety, and drug craving. The review suggested that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms. The USFDA does not indicate the presence of withdrawal symptoms following discontinuation of amphetamine use after an extended period at therapeutic doses.
Abuse of amphetamine mixed salts can result in a stimulant psychosis that may present with a variety of symptoms (e.g., paranoia, hallucinations, delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine abuse-induced psychosis states that about 5–15% of users fail to recover completely. The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis. Psychosis very rarely arises from therapeutic use.
Studies conducted on rodents and primates consistently observe long-term dopaminergic neurotoxicity with sufficiently high doses of amphetamine. The only proposed mechanism for neurotoxicity from high-dose amphetamine use in humans is indirect damage to dopamine terminals via autoxidation of dopamine, as opposed to direct toxicity from amphetamine. Nonetheless, in part due to clinical research ethics, there is no evidence that amphetamine mixed salts or racemic amphetamine is directly or even indirectly neurotoxic in humans, even at high doses. On the other hand, there is in vitro evidence that amphetamine is neurogenerative and neuroprotective from increasing the activity of the psychostimulant protein cocaine and amphetamine regulated transcript.
Contraindications, interactions, and precautions
- MAOIs (monoamine oxidase inhibitors, e.g., phenelzine, selegiline, iproniazid, etc.) —There is a high risk of a hypertensive crisis if amphetamine is administered within two weeks after last use of an MAOI type drug. Preliminary trials of low-dose amphetamine and MAOIs being administered together are in progress. However, this is to be done only under strict supervision of the prescribing parties.
- SSRIs (selective serotonin reuptake inhibitors, e.g., fluvoxamine, citalopram, paroxetine, etc.) — While a common combination, and although rare, the risk for serotonin syndrome exists. (Use only when directed)
- NRIs (norepinephrine reuptake inhibitors, e.g., atomoxetine, etc.) — NRI medications and amphetamine both enhance noradrenergic activity. Possible augmentation/potentiation of effects. (Use only when directed)
- SNRIs (selective serotonin-norepinephrine reuptake inhibitors) — See SSRIs and NRIs.
- Bupropion — Both bupropion and amphetamine have noradrenergic and dopaminergic activity. Bupropion is a potent CYP2D6 inhibitor. Bupropion has pro-convulsant properties that may be enhanced or cumulatively potentiated by amphetamine. (Use only when directed)
- Monoaminergic tricyclic antidepressant — See NRIs, SNRIs, and SSRIs. Possible potentiation of serotonin-, dopamine-, and/or norepinephrine-related drug effects. The combination of monoaminergic tricyclics and amphetamine compounds has been associated with increased sympathomimetic effects. The exceptions to this class (i.e. non-monoaminergic tricyclic antidepressants) include the glutamatergic tricyclic tianeptine and sigmaergic tricyclic opipramol.
- CYP2D6 (liver enzyme) inhibitors, e.g., Bupropion and most SSRIs such as fluoxetine, citalopram, paroxetine, etc. Some anti-psychotics such as thioridazine, haloperidol, and levomepromazine, as well as cocaine, the opioid agonist methadone, and others. It is important to determine if any medication or drug taken is a CYP2D6 inhibitor. Taking a CYP2D6-inhibiting drug along with amphetamine will lead to an elevated level of amphetamine in the system, resulting in the drug's remaining in the body for a longer period, which can lead to undesirable and possibly serious side effects.
- Individuals with pre-existing cardiac conditions or mental illnesses.
- Individuals with a history of drug abuse
Mechanism of action
Amphetamine has been identified as a potent agonist of trace amine-associated receptor 1 (TAAR1) (aka "TAAR1"), a GPCR, discovered in 2001, that is important for regulation of monoaminergic systems in the brain. Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits the function of the dopamine transporter, norepinephrine transporter, and serotonin transporter, as well as induce effluxion of these neurotransmitters. Amphetamine is a substrate for a specific neuronal synaptic vesicle uptake transporter called VMAT2. When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine, norepinephrine, and serotonin, among other monoamines, into the cytosol in exchange.
Dextroamphetamine (the dextrorotary enantiomer) and levoamphetamine (the levorotary enantiomer) have similar pharmacodynamics, but slightly different effects on the CNS and cardiovascular system. As a CNS stimulant, dextroamphetamine is roughly three to four times more potent than levoamphetamine, but levoamphetamine has stronger cardiovascular and peripheral effects. The overall greater potency of dextroamphetamine to central actions suggests that this form may have a higher potential for abuse. Levoamphetamine provides mixed amphetamine salts quicker onset and longer-lasting effects than dextroamphetamine alone. It has been reported that certain children have a better clinical response to levoamphetamine.
The half-life of amphetamine enantiomers differ and vary with age. The half life for dextroamphetamine is 9 hours for children of ages 6–12, 11 hours in adolescents aged 13–17, and 10 hours in adults. For levoamphetamine, the half-life is 11 hours for children of ages 6–12, 13–14 hours in adolescents aged 13–17, and 13 hours in adults. For both isomers, the immediate-release reaches peak plasma concentrations post-dose at 3 hours and the extended release variants at 7 hours. Amphetamine is eliminated renally with 30–40% of the drug being excreted unchanged at normal urinary pH. Amphetamine is a weak base with a pKa of 9–10; consequently, when the urinary pH is basic, more of the drug is in its free base form and less is excreted. When urine pH is abnormal, the urinary recovery of amphetamine may range from 1–75%, depending on whether urine is too alkaline or acidic respectively. Amphetamine is usually eliminated within 2 days of the last oral dose. Apparent half-life and duration of effect increase with repeated use and accumulation of drug.
Metabolism occurs mostly in the liver by the cytochrome P450 (CYP) detoxification system. CYP2D6 and flavin-containing monooxygenase are the only enzymes currently known to metabolize amphetamine in humans. Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamfetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone. Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine, 4‑hydroxynorephedrine, and norephedrine.
Related endogenous compounds
Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring molecules produced in the human body and brain. Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., identical molecular formula). In humans, phenethylamine is produced in the body directly from phenylalanine by the same enzyme that converts L-DOPA into dopamine, aromatic amino acid decarboxylase. In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, which the same enzyme that metabolizes norepinephrine into adrenaline. Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1; however, unlike amphetamine, both of these substances are broken down by monoamine oxidase, and therefore have a shorter half-life than amphetamine.
Detection in body fluids
Amphetamine mixed salts is frequently measured in urine or blood as part of a drug test in sports or employment, in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims, or to assist in the forensic investigation of a traffic or other criminal violation or a case of sudden death. Techniques such as immunoassay, which is the most common form of amphetamine drug test, may cross-react with a number of sympathomimetic drugs. Chromatographic methods specific for amphetamine are employed to prevent false positive results. Chiral-separation techniques may be employed to help distinguish the source of the drug, whether obtained legally from prescription amphetamine itself, prescription amphetamine prodrugs, (e.g., selegiline), and over-the-counter drug products (e.g., Vicks Vapoinhaler) or from illicitly obtained substituted amphetamines.
Amphetamine mixed salts is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for 2–4 days.
For the assays, a study noted that an enzyme multiplied immunoassay technique (EMIT) assay[note 3] for amphetamine and methamphetamine may produce a large number of false positives when compared with samples confirmed by liquid chromatography–tandem mass spectrometry. Moreover, gas chromatography–mass spectrometry (GC–MS) of amphetamine and methamphetamine with the derivatizing agent (S)-(-)-trifluoroacetylprolyl chloride allows for the detection of methamphetamine in urine. In comparison, GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent Mosher's acid chloride[note 4] allows for the detection both of dextroamphetamine and dextromethamphetamine in urine. Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the aforementioned forms of legal and illicit drug use.
Adderall is available as an instant-release (IR) and an extended-release (XR) drug. Adderall instant-release is manufactured today by Teva and Barr Pharmaceuticals. Shire Pharmaceuticals, the creator of Adderall IR, no longer produces it. However, Shire does continue to manufacture the extended-release version of Adderall ("Adderall XR"). Richwood Pharmaceuticals (later merged with Shire) introduced the Adderall brand in 1996 in the form of a multi-dose, instant-release tablet derived from an original formula of the weight management drug Obetrol. In 2006, Shire agreed to sell rights to the Adderall name for this instant-release medication to Duramed Pharmaceuticals DuraMed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 when Teva completed its acquisition of Barr Pharmaceuticals (including Barr's Duramed division). Therefore, following its acquisition of Duramed, Teva is in the somewhat unusual position of manufacturing both a generic formulation of Adderall instant-release (under its Barr Division) as well as "brand name" Adderall (under its DuraMed division.)
In 2001, Shire introduced an extended-release preparation of these ingredients in a variety of dosages under the brand name "Adderall XR," on which Shire retains exclusive patent rights until the patent expires, expected in 2018. Shire was unable to extend patents by evergreening and generic version of Adderall XR became available in 2009. In 2009, Barr and Shire reached a settlement agreement permitting Barr to offer a generic form of the drug beginning April 1, 2009.
Manufacturer's claims of instant release have been disputed. A US patent granted for Adderall was a pharmaceutical composition patent listing a rapid immediate-release oral dosage form. No claim of increased or smooth drug delivery was made. A study by James and colleague as published in the November 2001 issue of the Journal of the American Academy of Child and Adolescent Psychiatry, placebo-controlled crossover study conducted among 35 children ages 5–12 indicated that patients behaved similarly to those having taken other immediate-release amphetamines. The authors found that sustained-release dextro-amphetamine (the main isomeric-amphetamine component of Adderall) had a longer duration of action; however, D-amphetamine was less effective in the first few hours.
Rexar, a pharmaceutical company, reformulated another drug, branded as Obetrol, to exclude methamphetamine and continued to sell this new formulation under the same brand name. This new unapproved formulation was later rebranded and sold as Adderall by Richwood after it acquired Rexar resulting in FDA warning in 1994. Richwood submitted this formulation as NDA 11-522 and Adderall gained FDA approval for the treatment of attention-deficit/hyperactivity disorder therapy on February 13, 1996.
- amphetamine aspartate monohydrate (racemic - i.e. 50% dextroamphetamine and 50% levoamphetamine)
- amphetamine sulfate (racemic)
- dextroamphetamine sulfate
- dextroamphetamine saccharate
Amphetamine mixed salts are available in immediate release and extended release formulations. The immediate release formulation is indicated for use in ADHD and narcolepsy,. The extended release formulation only approved for the treatment of ADHD.
- In Canada, amphetamines are in Schedule I of the Controlled Drugs and Substances Act, and can only be obtained by prescription.
- In Japan, the use, production, and import of any medicine containing amphetamine are prohibited.
- In South Korea, amphetamines are prohibited.
- In Thailand, Amphetamines are classified as Type 1 Narcotics.
- 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 United States, amphetamine is a Schedule II prescription drug, classified as a CNS (central nervous system) stimulant.
- Internationally (United Nations), amphetamine is in Schedule II of the Convention on Psychotropic Substances
- Enantiomers are molecules that are "mirror images" of one another; they are structurally identical but of the opposite orientation, like left and right hands. "Amphetamine" refers to equal parts of the enantiomers, i.e. 50% levoamphetamine and 50% dextroamphetamine.
- The study specified the EMIT II Plus Monoclonal Amphetamine/Metamphetamine assay.
- Mosher's acid chloride is also known as (S)-(+)-α-methoxy-α-(trifluoromethy)phenylacetyl chloride.
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• Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
• Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
• Improved reaction time
• Increased muscle strength and delayed muscle fatigue
• Increased acceleration
• Increased alertness and attention to task"
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The prevalence of this withdrawal syndrome is extremely common (Cantwell 1998; Gossop 1982) with 87.6% of 647 individuals with amphetamine dependence reporting six or more signs of amphetamine withdrawal listed in the DSM when the drug is not available (Schuckit 1999)...Withdrawal symptoms typically present within 24 hours of the last use of amphetamine, with a withdrawal syndrome involving two general phases that can last 3 weeks or more. The first phase of this syndrome is the initial “crash” that resolves within about a week (Gossop 1982;McGregor 2005)..."
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Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 220.127.116.11) (Berry, 2004) (Fig. 2)...It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone...
Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines. It is not often realized, however, that this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut...
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