What is adderall?
Adderall is a potent amphetamine psychostimulant and pharmaceutical drug used for the treatment of attention deficit and hyperactivity disorder (ADHD) and narcolepsy. The active ingredients are salts of racemic amphetamine and dextroamphetamine.
At the moment, there is one product on the market, released in 2013, which contains dextroamphetamine (right or right enantiomer) and levoamphetamine (left or left enantiomer) in a ratio of 3:1. Adderol is available in twovariants: immediate release and prolonged release.
Use of Adderall
Adderall is typically used to treat ADHD and narcolepsy, two diseases for which the US FDA has approved its use. However, the drug is sometimes prescribed for other diseases, such as depression, but not for its intended purpose.
Adderall is also used to treat obesity, but The American society of health system Pharmacists does not recommend such use.
In 2011, Americans between the ages of 20 and 39 received nearly 14 million monthly prescriptions to treat the disease, which is two and a half times more than 5.6 million. just four years earlier, according to IMS Health. In primates, long-term use of amphetamine during puberty does not have a noticeable negative effect on the physiology, behavior or development of the dopamine system.
How Long Can Adderall Be Detected in Urine
The Key active ingredient in Adderall is dextroamphetamine. The half-life of this drug is 10 hours. This means that after 10 hours, half of these dextroamphetamine will be removed from the body. The quantity that remains from an average dose is going to be broken down in and excreted in around three days.
Whether or not Adderall is detected in the body in this time depends on the form of evaluation that’s used. Urine testing is a frequent way of measuring the amount of a drug in someone’s system, however, Adderall can also be seen in blood, saliva, and hair.
Adderall detection period based on the process of drug testing:
Urine: Adderall can be found in urine for 3 times but might not be detectable for 3 hours following ingestion.
Blood: Adderall is found in the blood for about 24 hours.
Hair: Adderall can be detected in hair follicles around a month, but may not be present until a week.
Saliva: Adderall can be stay in saliva for 48 hours.
Attention deficit hyperactive disorder
The U.S. Agency for health and medical quality research conducted a study on the comparative effectiveness of treatments for children with ADHD, including various amphetamine-type drugs, and summarized the results for parents.
It has been shown that amphetamines can reduce the manifestation of symptoms ADHD in children under the age of six years, however, to confirm these data at the present time there is not sufficient evidence.
In the future, it is necessary to study the use of the drug for young children and for more than a year. Adderol has also been shown to reduce the risk of ADHD in adults, but research is limited.
According to Millchap et al., ” a Multicenter, placebo-controlled study of the treatment of ADHD with amphetamines in Sweden showed that patients showed significant improvements in indicators such as attention, hyperactivity and destructive behavior. The average change in intelligence was 4.5 after more than 9 months of therapy.”
However, the authors note that patients in the study had a surprisingly high incidence of concomitant disorders associated with ADHD. Consequently, subsequent trials of stimulants in the treatment of ADHD with a lower risk of comorbidities are expected.
Adderall: the way of application and dose
Adderol is available in forms of immediate and prolonged release. Prolonged release capsules are usually used in the morning.
Forms-generics are available in different dosing options. Long-release formulas are available under the brand name Adderall XR, and are designed to provide therapeutic effects and plasma concentrations identical to two doses taken at intervals of 4 hours.
In therapeutic doses, psychostimulants, including amphetamines, increase performance when passing memory tests, which is observed in both healthy individuals and patients with ADHD.
In addition, these stimulants also increase sexual arousal and affect the nucleus accumbens, increasing productivity in complex and time-consuming tasks. It is connected with the use of amphetamine drugs by College and high school students as “doping” during the tests during the school year.
Based on the data of studies of independent illegal use of stimulants among students, it was shown that students use stimulants to increase productivity, and not for recreational use.
In doses significantly higher than medical ones, stimulants can affect working memory and cognitive control. Because of its strong stimulant effects, amphetamines are also sometimes used in some sports.
However, in competitive sports such use is generally prohibited by the anti-doping rules. In moderate therapeutic doses, amphetamine helps to increase physical strength, acceleration, endurance, while reducing reaction time.
Similar to methylphenidate and bupropion, amphetamine increases endurance in humans, primarily by inhibiting dopamine reuptake in the Central nervous system. Very high doses of amphetamine can cause side effects such as acute skeletal muscle necrosis and hyperthermia, reducing athletic performance.
While the risk of addiction in recreational use and abuse of amphetamine is high, in typical medical use the risk is unlikely.
With the abuse of amphetamine, tolerance develops rapidly; therefore, with prolonged use of the drug, to achieve the same effect, it is necessary to increase the amount of the drug.
According to a review by Cochrane Collaboration on drug withdrawal in individuals who are heavily dependent on amphetamine and methamphetamine, “with the sudden discontinuation of amphetamine in regular users, many have a time-limited withdrawal syndrome within 24 hours of the last dose.”
The review notes that withdrawal syndrome is often observed in regular users taking high doses of the drug, and occurs in 87.6% of cases, persisting for 3-4 weeks with a phase of “withdrawal” during the first week.
Symptoms of amphetamine syndrome may include fatigue, dysphoric mood, increased appetite, vivid or lucid dreams, increased drowsiness or insomnia, increased or decreased mobility, anxiety, and the development of cravings for the drug.
In the review, the assumption is that the withdrawal symptoms associated with dependency that suggests that the therapeutic use is associated with a much more mild withdrawal symptoms. The USFDA does not indicate withdrawal symptoms after discontinuation of amphetamine use after a long period of therapeutic doses.
Abuse of Adderol can lead to the development of stimulant psychosis, which can be represented by various symptoms (such as paranoia, hallucinations and delirium).
A review of Cochrane Collaboration on the treatment of amphetamine -, dextroamphetamine-and methamphetamine-related psychosis shows that about 5-15% of users are unable to fully recover.
The same review shows that, based on at least one trial, antipsychotic drugs have been shown to effectively reduce the symptoms of acute amphetamine psychosis. With the therapeutic use of amphetamine, the development of psychosis is unlikely.
Studies conducted on rodents and primates have consistently shown the presence of long-term dopaminergic neurotoxicity when taking sufficiently high doses of amphetamine.
The only proposed mechanism of neurotoxicity in high doses of amphetamine in humans is indirect damage to dopamine terminals through dopamine auto-oxidation, as opposed to direct amphetamine toxicity.
However, due in part to the ethics of clinical research, there is no evidence that Adderol or racemic amphetamine can directly or even indirectly cause neurotoxic effects in humans, even when taken in high doses. On the other hand, there is evidence from in vitro studies that amphetamine is a neurodegenerative and neuroprotective drug, which is associated with an increase in the activity of psychostimulatory protein cocaine and amphetamine transcript.
Contraindications, drug interactions and precautions
MAO inhibitors (monoamine oxidase inhibitors such as Phenelzine, Selegiline, Iproniazid, etc.) – there is a high risk of hypertensive crisis if amphetamine is administered within two weeks of the last use of the IMAO drug.
Preliminary trials are under way for the co-administration of low-dose amphetamine with IMAO. However, such reception should be carried out only under close supervision of the attending physician.
SSRIs (selective serotonin reuptake inhibitors such as Fluvoxamine, Paroxetine, etc.) – there is a risk of serotonin syndrome (use only as directed by a physician).
IOSN (norepinephrine reuptake inhibitors, for example, Atomoxetine, etc.) – IOSN and amphetamine cause an increase in noradrenergic activity. May increase / potentiate effects (use only as directed by a physician).
CISSN (selective reuptake inhibitors of serotonin and norepinephrine) – see SSRIs and ISN.
Bupropion-Bupropion and amphetamine cause increased noradrenergic and dopaminergic activity. Bupropion is a potent CYP2D6 inhibitor. Bupropion has Pro-convulsive properties that can be enhanced or cumulatively potentiated by amphetamine (use only as directed by a physician).
Monoaminergic tricyclic antidepressants – the SSRIS see, CISSN and SSRIs. It is possible to potentiate the effects of serotonin, dopamine and/or noradrenaline preparations. The combination of monoaminergic tricycles and amphetamine compounds is associated with an increase in sympathomimetic effects.
Exceptions to this class (i.e., non-monoaminergic tricyclic antidepressants) include the glutamatergic tricyclic drug Tianeptin and the tricyclic drug Opipramol.
Inhibitors of CYP2D6 (liver enzyme), e.g., Bupropion and most SSRIs such as Fluoxetine, Citalopram, Paroxetine, etc. Some antipsychotic drugs such as Thioridazine, Haloperidol, and Levomepromazine, as well as cocaine, the opioid agonist Methadone, and others. It is important to determine whether the drug or drug you are taking is a CYP2D6 inhibitor.
Co – administration of drugs inhibiting CYP2D6 with amphetamine can lead to increased levels of amphetamine in the system, causing an increase in the time of the presence of the drug in the body, which can lead to undesirable and possibly serious side effects.
Mechanism of action
Amphetamine enters the presynaptic nerve cell across the neuronic membrane or through digital audiotape. Once within, it binds to TAAR1 or enters conjunction vesicles through VMAT2. When binding amphetamine to TAAR1, the pulsation frequency of the dopamine receptor decreases and signaling of protein kinase a and protein kinase C is triggered, thereby providing phosphorylation of DAT.
The phosphorylated DAT then either acts backwards or goes into the presynaptic neuron and stops the transport. When amphetamine enters synaptic vesicles through VMAT2, dopamine is released into the cytosol (yellow zone).
Amphetamine has been identified as a potent agonist of the amine-bound receptor 1 (TAAR1) (or “TAAR1”), a receptor associated with G-protein discovered in 2001, which plays an important role in regulating monoaminergic systems in the brain. Activation of TAAR1 increases camp production through activation of adenyl cyclase.
Activation of TAAR1 also reduces the postsynaptic pulsation frequency, and through protein kinase signaling inhibits the function of the dopamine Transporter, norepinephrine Transporter and serotonin Transporter, and contributes to the release of these mediators.
Amphetamine is a substrate for a specific neural synaptic Transporter called VMAT2. When VMAT2 takes amphetamine, the vesicles release dopamine, norepinephrine and serotonin and other biogenic amines into the cytosol in exchange.
Dextroamphetamine (right-handed enantiomer) and levoamphetamine (left-handed enantiomer) have the same pharmacodynamics but different affinity of binding to biomolecular targets. Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.
Thus, dextroamphetamine about three to four times more stimulates the Central nervous system than levoamphetamine. However, levoamphetamine has slightly more pronounced cardiovascular and peripheral effects.
Levoamphetamine provides Aderol with faster onset of action and longer lasting effects than dextroamphetamine. Some children were reported to have a better clinical response to levoamphetamine.
Related endogenous compounds
Amphetamine has a very similar structure and function to endogenous trace amines, natural molecules produced in the human body and brain. Among this group, the most closely related compounds are phenethylamine, the original amphetamine compound,and N-methylphenethylamine, an amphetamine isomer (i.e., having an identical molecular formula).
In humans, phenethylamine is produced directly from phenylalanine by an enzyme that converts L-DOPA to dopamine, an aromatic amino acid called decarboxylase. In turn, N-methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, an enzyme that converts norepinephrine into adrenaline.
Like amphetamine, phenethylamine and N – methylphenethylamine regulate monoamine neurotransmission through TAAR1; however, unlike amphetamine, both substances are destroyed by monoamine oxidase and therefore have a shorter half-life than amphetamine.
Amphetamine enantiomers have a different half-life, which depends on the age of the person. The half-life of dextroamphetamine is 9 hours for children 6-12 years, 11 hours for adolescents 13-17 years and 10 hours for adults.
The half-life of levoamphetamine is 11 hours for children 6-12 years, 13-14 hours for adolescents 13-17 years, and 13 hours for adults. Both isomers of the formula immediate-release reaches peak concentrations in plasma after 3 hours post-dose and the extended-release formula – 7 hours.
Amphetamine is excreted by the kidneys, while 30-40% of the drug is excreted unchanged at normal urine pH. Amphetamine is a weak base with RCA 9-10; hence, when the urine pH is basic, most of the drug is in the form of a free base and is less secreted.
With abnormal urine pH, the urinary recovery of amphetamine can vary from 1 to 75%, depending on whether the urine Ph is too alkaline or acidic, respectively. Amphetamine is usually excreted within 2 days of the last oral administration. The full half-life and duration of the effect increase with repeated use and accumulation of the drug in the body.
Metabolism occurs mainly in the liver via the cytochrome P450 detoxification system (CYP). CYP2D6 and flavin-containing monooxygenase are the only currently known enzymes capable of metabolizing amphetamine within the human body.
Amphetamine has a range of metabolic products derived from the body, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine and phenylacetone.
Among these metabolites active sympathomimetics are 4-hydroxyamphetamine, 4-hydroxynorephedrine and norephedrine. Major metabolic pathways include aromatic para-hydroxylation, aliphatic alpha – and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.
The main active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine; however, most of the administered dose is excreted in the form of amphetamine and inactive metabolites.
Detection in biological fluids
The presence of amphetamine in urine or blood is checked often in the framework of doping control in sports or in employment, as well as in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims or to assist in the course of forensic medical examination in cases of poisoning or other criminal violation or a sudden death.
Methods such as immunological analysis, which is the most common form of amphetamine testing, may cross-react with a number of sympathomimetic drugs. Chromatography techniques specific to amphetamine are used to prevent false positives.
Chiral separation techniques can be used to identify the source of a drug, whether it was obtained legally from prescription amphetamine, prescription amphetamine prodrugs (e.g., selegiline), and over-the-counter drugs (e.g., Vicks Vapoinhaler) or from illegally obtained substituted amphetamines.
Amphetamine is usually only detected by a standard test for about 24 hours, although high doses of amphetamine can be detected within 2-4 days after administration.
The study notes that the enzyme multiple immunoassay technique of amphetamine and methamphetamine may be associated with a large number of false positive results, compared with samples confirmed by liquid chromatography – tandem mass spectrometry.
In addition, gas chromatography – mass spectrometry (GC-MS) of amphetamine and methamphetamine with derivatizing substance (S)-(- )- TRIFLUOROACETYL chloride, allows to detect the presence of methamphetamine in urine.
For comparison, GC-MS of amphetamine and methamphetamine with the chiral derivatizing substance masterovoy chloride of the acid allows to detect dextroamphetamine and dextromethamphetamine in the urine.
Thus, the latter method can be used on samples tested positively by other methods to help distinguish between theseforms of legal and illegal drug use.
History of Adderall
Adderol is available in the form of instant drugs (IR) and prolonged (XR) release. As of December 2013, ten different companies at the same time prepared a generic adderall is instant release, while Teva Pharmaceutical Industries, Actavis, and Barr Pharmaceuticals currently manufacture generic Adderall XR of.
Shire PLC, the company that holds the original patent for Adderall and Adderall XR, still produces Adderall XR, but not Adderall IR.
Richwood Pharmaceuticals, which later merged with Shire PLC, introduced the current Adderall brand in 1996 as an instant release pill. In 2006, Shire agreed to sell the rights to the Adderall brand for this instant drug to Duramed Pharmaceuticals. Duramed Pharmaceuticals was acquired by Teva Pharmaceuticals in 2008 when Teva completed its acquisition of Barr Pharmaceuticals, including the Barr division, Duramed.
The first generic drug Adderall IR was introduced to the market in 2002. Later, in 2009, Barr and Shire reached a settlement agreement, under which Barr was given the right to sell the generic drug, starting April 1, 2009.
The manufacturer’s claims for the immediate release version have been challenged. The us patent granted to Adderol was a pharmaceutical patent for an oral dosage form of immediate release.
A study by James and colleagues, published in November 2001 in the Journal of The American Academy of child and Adolescent Psychiatry, a placebo-controlled cross-study among 35 children aged 5 to 12 years, showed that patients behaved in the same way as patients who received other amphetamines of immediate release.
The authors found that delayed-release dextro-amphetamine (the main isomer amphetamine component of Adderol)had a longer life, but D-amphetamine was less effective in the first few hours.
The pharmaceutical company Rexar has changed the formula of another drug, with the brand name Obetrol, to exclude methamphetamine and continue to sell this new formula under the same brand name.
This new that have not been approved formula, was later renamed and sold under the brand name adderall company from Richwood after the company was acquired Rexar, with the result that, in 1994, the company received from the FDA warning.
Richwood introduced this formula called NDA 11-522 and on February 13, 1996, adderall received FDA approval for the treatment of attention deficit hyperactivity disorder. Currently, in the United States, Adderol is used primarily for the treatment of ADHD and narcolepsy.
Adderol is a mixture of amphetamine salts, consisting of equal amounts by weight:
• amphetamine aspartate monohydrate (racemic-i.e. containing 50% dextroamphetamine and 50% levoamphetamine)
• amphetamine sulfate (racemic)
• dextroamphetamine sulfate
• dextroamphetamine of sugar
This mixture has a slightly more pronounced effect on the Central nervous system than racemic amphetamine, due to a higher proportion of dextroamphetamine. Adderall is available in formulas for immediate and extended release.
The immediate release formula is indicated for use in ADHD and narcolepsy. The prolonged release formula is approved only for the treatment of ADHD.