Adderall

Adderall is a pharmaceutical psychostimulant comprising mixed amphetamine salts. The drug is used primarily to treat attention-deficit hyperactivity disorder and narcolepsy. Adderall has also been used successfully to manage severe cases of treatment-resistant depression. It is a Schedule II controlled substance, meaning that it has been deemed to have a high potential for abuse and addiction despite genuine medical uses.

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History

Brand name Adderall was introduced in 1996 in the form of a multi-dose, instant-release tablet that came from the original formula which was used in weight management Obetrol. It has since become available in a generic formulation of "mixed amphetamine salts". The active ingredients of Adderall include a combination of dextroamphetamine and racemic d/l-amphetamine salts. Shire Pharmaceuticals later introduced an extended-release preparation of these ingredients in a variety of dosages, under the brand name "Adderall XR" (extended release), on which Shire still retains exclusive patent rights until 2009.

Chemistry

Specifically, Adderall XR is composed of the following proportions of active ingredients:

• 1/4 dextroamphetamine saccharate
• 1/4 dextroamphetamine sulfate
• 1/4 aspartate (racemic dextro/laevo-amphetamine)
• 1/4 sulfate (racemic dextro/laevo-amphetamine)

These four salts are metabolized at different rates and possess diverse half lives, therefore resulting in a less dramatic onset and termination of therapeutic action; as compared to single salt amphetamine preparations.

The average elimination half-life in adults for dextroamphetamine is 10 hours and 13 hours for l-amphetamine. Breakdown rates are affected by urinary and stomach pH, weight, gender, other medications, and age in the direction of +/- roughly 2 hours. Its effects are similar to other CNS stimulants of the same class and preparation (see amphetamine for details).

Urinary and stomach pH levels can significantly affect (d,l)-amphetamine excretion and absorption. Co-administration of acidic substances (eg; citric acid) causes an accelerated excretion of (d,)-amphetamine while co-administration of alkaline agents (eg; antacids) causes a marked increase in both retention and absorption of amphetamines sometimes resulting in dangerously high amphetamine levels. For example, taking the pill with orange juice will cause the accelerated excretion, making the dose possibly ineffective.

Dosing and administration

Adderall is marketed as either an immediate-release tablet, Adderall, or an extended-release capsule, Adderall XR ("eXtended Release"). Doses for the immediate-release tablet come in 5, 7.5, 10, 12.5, 15, 20, and 30 milligram strengths. Doses for the extended-release capsule come in 5, 10, 15, 20, 25, and 30 milligram strengths.

Adderall XR utilizes the Microtrol extended-release delivery system, incorporating two types of beads. The first dissolves immediately, releasing half of the medication, while the second type dissolves much more slowly releasing the remaining medication four hours later. Maximum plasma concentration is achieved in seven hours, compared to regular Adderall, which reaches maximum plasma concentration within three hours. As a result of its high bioavailability, Adderall XR's effectiveness is not altered by food absorption in the gastrointestinal tract. However, mean plasma concentration is prolonged by 2.5 hours (using a standard high-fat meal as the control). Medications that alter urinary pH will cause variations in amount and method of excretion and usage should be monitored when taken concurrently with Adderall.^[1]

Manufacturer's claims of instant release have been disputed. A patent application for Adderall^[2] was a pharmaceutical composition patent listing a rapid immediate release oral dosage form. No claim of increased or smooth drug delivery was made. A recent double-blind, placebo-controlled crossover study, conducted among children, indicated that patients behaved similarly to other immediate release amphetamines. The authors found that sustained-release dexamphetamine (the main isomeric-amphetamine component of Adderall) had a longer duration of action, though dextro-amphetamine was less effective in the first few hours.^[3]

Generic equivalents/alternatives

A generic version some of the main components of Adderall is dextroamphetamine sulfate. Dextroamphetamine sulfate, also known as Dexedrine, is available in a sustained release form as a generic. The savings between Adderall XR and generic Dexedrine ER are significant: 90 dextroamphetamine extended-release capsules cost $20 at a big box retail pharmacy in the United States, while the equivalent 90 Adderall XR® capsules cost $270. The difference, according to some pharmacists, is due to advertising costs for Adderall XR®'s replacement from the same company, Vyvanse,^{[citation needed]} which is—according to some—in and of itself, a derivative of a derivative of Dexedrine.

It should be noted that, officially, the actual generic equivalents of Adderall are "mixed amphetamine salts". A generic extended-release form is yet not available due to patent prohibitions. Dexedrine (dextroamphetamine sulfate) is one component of several active drugs in Adderall and therefore Dexedrine ER is not a strict generic equivalent for Adderall XR, though it may, in terms of physiological and psychological effects, be a de facto generic alternative. Vyvanse is a derivative of Dexedrine, yet it behaves differently in the body (see Dextroamphetamine at "Formulations"). The manufacturer has added extra ingredients (in the case of Adderall) or created a prodrug (a precursor) of dextroamphetamine (in the case of Vyvanse) in order to patent allegedly "improved" products that are similar to Dexedrine yet cannot be produced generically for the time being.

Mechanism of action

Amphetamines, both as dextroamphetamine and levoamphetamine (or a racemic mixture of the two enantiomers), are believed to exert its effects by binding to the monoamine transporters and increasing extracellular levels of the biogenic amines dopamine, norepinephrine and serotonin.

It is hypothesized that d-amphetamine acts primarily on the dopaminergic systems, while l-amphetamine is comparatively norepinephrinergic. The primary reinforcing and behavioral-stimulant effects of amphetamine, however, are linked to enhanced dopaminergic activity, primarily in the mesolimbic DA system. Amphetamine binds to the dopamine transporter (DAT) and blocks the transporters ability to clear DA from the synaptic space. In addition, amphetamine is transported into the cell which leads to dopamine efflux (DA is transported out of the cell and into the synaptic space via reverse transport of the DAT).

Amphetamine also possesses the ability to inhibit the enzymes monoamine oxidase A and B (MAO-A and MAO-B) in high doses. MAO-A is responsible for the break down of serotonin, dopamine, norepinephrine and epinephrine. MAO-B is responsible for breaking down dopamine (more potently than MAO-A) and phenylethylamine (PEA), which has actions similar to amphetamine itself and is thought to be involved in feelings of lust, confidence, obsession and sexuality. Some of the first antidepressants successfully marketed are in fact Monoamine Oxidase inhibitors. However, MAO inhibition seen with amphetamine is neither substantial enough in duration and quantity to entail the need for a tyramine limited diet, unlike the more potent and long lived MAO inhibiting antidepressants.

Amphetamine's ability to cause the inhibition of MAO results in the accumulation of monoamines while amphetamine also directly stimulates the release of these neurochemicals, resulting in a potent elevation in monoamine neurotransmission.

Double-blind, placebo-controlled studies of dextroamphetamine in prepubertal subjects have shown significant performance increases on cognitive tasks and decreased reaction time.^[4]

Amphetamines have been shown to pass through into breast milk. Because of this, mothers taking medications containing amphetamines are advised to avoid breastfeeding during their course of treatment.^[5]

Side effects

In children

• Decreased appetite^[1]
• Difficulty falling asleep^[1]
• Stomachache^[1]
• Emotional lability^[1]
• Dry mouth^[1]

In adults

• Dry mouth^[1]
• Loss of appetite^[1]
• Difficulty falling asleep^[1]
• Weight loss
• Symptoms of Depression/Anxiety

From overdose

These symptoms require immediate medical assistance:

• Symptoms of tourettism^[1]
• Aggression^[1]
• Symptoms of depression^[1]
• Seizures or abnormal EEGs^[1]
• High blood pressure^[1]
• Tachycardia
• Swelling of hands/feet/ankles (for example, numbing of the fingertips)
• Delusions
• Sweating
• Vomiting
• Dehydration
• Unexplained muscle pain
• Lower abdominal pain

Adderall abuse

Tolerance, extreme psychological dependence, and severe social disability can occur when amphetamines are abused. The manufacturer warns against exceeding the prescribed dosage, injecting the drug, or insufflation of the drug. Prolonged high doses of amphetamines followed by an abrupt cessation can result in extreme fatigue and mental depression. Chronic abuse of amphetamines can manifest itself as psychosis, often indistinguishable from schizophrenia.^[1]

Contraindications, interactions, and precautions

The following provides only general guidelines and is not comprehensive. Please refer to a more comprehensive list for further information regarding co-administration of amphetamine with other substances.

• SSRIs (selective serotonin reuptake inhibitors) — While rare, the possibility for serotonin syndrome exists with this combination. Use only when it is directed. eg; Fluoxetine, Citalopram, Paroxetine, etc.
• NRIs (norepinephrine reuptake inhibitors) — NRI medications and amphetamine both enhance noradrengic activity. Possible augmentation/potentiation of effects. Use only when directed. eg; Atomoxetine (Strattera)
• SNRIs (selective serotonin-norepinephrine reuptake inhibitors) — See SSRIs and NRIs.
• Bupropion — Both bupropion and amphetamine have noradrengic and dopaminergic activity. Possible augmentation/potentiation of effects. Bupropion has pro-convulsant properties that may be enhanced or cumulatively potentiated by amphetamine.(eg; bupropion (Wellbutrin IR, SR, XL) and (Zyban) etc.) Use only when directed.
• MAOIs (monoamine oxidase inhibitors) — Do not administer amphetamines for a minimum of 2 weeks after last use of MAOI type drug. Possible hypertensive crises, dangerously elevated amphetamine levels. (eg; Phenelzine (Nardil), Selegiline (Emsam), Iproniazid (Iprozid) etc.) There are preliminary trials of low dose amphetamine and MAOIs being administered together; however, this is to only be done under strict supervision of the prescribing parties.
• Tricyclics (tricyclic antidepressants) — See SNRIs and SSRIs. Possible potentiation of 5htp (serotonin), dopamine and norepinephrine related drug effects. Use only when indicated. (eg; Imipramine (Tofranil, Janamine) etc.)

Performance-enhancing use

Adderall has also been used as an off-label drug for weight loss. A doctor and the creator of The Adderall Diet began prescribing adderall to 800 teens for weight loss. Adderall’s side effect of weight loss and appetite suppression is a desired result for those trying to lose weight. There have not been any scientific studies performed to evaluate the effectiveness of this form of treatment and is viewed as a very risky and potentially dangerous way to shed pounds.^[6]

Professional poker player Paul Phillips claimed that the use of Adderall and other medications prescribed to him for ADHD treatment made him a much better player and helped him earn more than $2.3 million in poker. The drugs improved his concentration during high-stakes tournaments, he said, allowing him to better track all the action at his table.^[7]

Government warnings

On February 9, 2005, Health Canada suspended all sales of Adderall XR after data collected by manufacturer Shire Pharmaceuticals linked the drug to 12 sudden deaths in American children between the years of 1999 to 2003.^[8] Further research, however, found little data suggesting use of Adderall resulted in an increased risk of cardiac defect. Of the twelve sudden deaths positively linked to pediatric Adderall users during the four-year period, five had known pre-existing cardiac conditions, one died after strenuous exercise in 110-degree heat and two had levels suggestive of an overdose. Given the more than 37,000,000 prescriptions for Adderall filled during the four years, the U.S. Food and Drug Administration could find no increased risk of sudden death among Adderall users beyond the normal rate of the general population.^[9][10] In August 2005, Health Canada followed the committee report of three independent physicians and lifted the ban on Adderall XR.^[11][12] Given that persons with ADHD are more likely to engage in risky or dangerous behavior, it has been suggested that stimulant medications for persons with ADHD may actually result in lower incidence of premature death.^[13] The use of Adderall is generally not advised in those persons with pre-existing cardiac or mental illnesses. It is also not advised in persons who have a history of drug abuse.^[14] Although FDA safety advisors voted 8 to 7 to issue a black box warning, the FDA's pediatric advisory committee refused to give the drug its most severe black box warning in March 2006.^[15] A Black Box Warning regarding amphetamine abuse potential is in place, however.

Notes and references

Further reading

• Hanna, Mohab "Making the Connection: A Parent's Guide to Medication in AD/HD" Ladner-Drysdale 2006