Amphetamines General Statement (Monograph)

Drug class: Amphetamines
VA class: CN801

Introduction

Amphetamines exhibit pharmacologic actions that include CNS and respiratory stimulation and sympathomimetic effects.

Uses for Amphetamines General Statement

Amphetamines are used as stimulants to decrease daytime sleepiness in the management of narcolepsy. Amphetamines also are used as adjuncts to psychological, educational, social, and other remedial measures in the treatment of attention-deficit/hyperactivity disorder (ADHD). Certain amphetamines also are used for the treatment of binge-eating disorder. In addition, certain amphetamines are used as adjuncts to caloric restriction and behavioral modification in the short-term treatment of exogenous obesity. However, short-term or intermittent therapy with anorexigenic drugs is unlikely to maintain a long-term benefit, and prolonged administration of amphetamines for the treatment of obesity is not recommended. Amphetamines, particularly methamphetamine, have been misused and abused for their CNS stimulatory effects.

Narcolepsy

Amphetamines are used as stimulants to decrease daytime sleepiness in the management of narcolepsy. Amphetamines should not be used to combat fatigue or exhaustion or to replace sleep in normal individuals.

Amphetamines remain the mainstay of treatment for narcolepsy based on a long record of clinical experience. However, because most clinical trials have involved small numbers of patients, the risk-to-benefit remains to be further established.

In determining the most appropriate stimulant therapy for a given patient, clinicians should consider benefit-to-risk (including adverse effect profile), drug cost, convenience of administration, and cost of ongoing care (including the possible need for laboratory monitoring).

Patients who fail to respond to an adequate trial of stimulant drug therapy should be assessed carefully for other possible causes of excessive sleepiness such as insufficient sleep, inadequate sleep hygiene, circadian rhythm disorders, obstructive sleep apnea syndrome, or periodic limb movement disorder.

Tolerance to the clinical effects may develop with long-term therapy, particularly at high dosages.

Narcolepsy rarely occurs in children younger than 12 years of age, and the relative safety and efficacy of various stimulant drugs in this age group remains to be elucidated. Although amphetamines can be used for narcolepsy occurring in children, methylphenidate appears to be used most commonly based principally on extensive experience with the drug in pediatric patients with ADHD.

Attention-Deficit/Hyperactivity Disorder

Amphetamines also are used as adjuncts to psychological, educational, social, and other remedial measures in the treatment of ADHD (hyperkinetic disorder, hyperkinetic syndrome of childhood, minimal brain dysfunction) in children, adolescents, and adults. Almost all studies comparing behavioral therapy versus stimulants alone have shown a much stronger therapeutic effect from stimulants than from behavioral therapy, and stimulants (e.g., methylphenidate, amphetamines) remain the drugs of choice for the management of ADHD. For a more detailed discussion on the management of ADHD, including the use of stimulants such as amphetamines, see Uses: Attention Deficit Hyperactivity Disorder, in Methylphenidate 28:20.32.

Few, if any, differences have been found between amphetamines (e.g., dextroamphetamine), methylphenidate, or pemoline (no longer commercially available in the US) or various dosage forms (short-, intermediate-, or long-acting formulations) of the drugs in short-term clinical studies in children with ADHD, and the choice of stimulant therapy should be individualized. Because hepatic toxicities have been associated with pemoline, some experts recommended its use only in patients who failed to respond to adequate trials of methylphenidate and an amphetamine, as well as adequate trials of second-line therapies (e.g., tricyclic antidepressants, bupropion). However, in 2005, the US Food and Drug Administration (FDA) determined that the risk of hepatic toxicity associated with the drug outweighs its benefits and the drug no longer is commercially available in the US.

Short-term and longer-term (up to 14 months’ duration) studies have shown unequivocal beneficial effects of the stimulants on the defining core symptoms of ADHD (attention and concentration, activity, distractability, impulsivity) and associated aggressiveness during continued therapy with the drugs. Children who fail to show positive therapeutic effects or who experience intolerable adverse effects with one stimulant should be tried on an alternative stimulant since most such children will exhibit a positive response to alternative stimulants and current evidence from crossover studies supports the efficacy of different stimulants in the same child; likewise, children who fail an adequate trial of 2 stimulants should be tried on a third type or formulation of stimulant. However, stimulants usually do not normalize the entire spectrum of behavioral problems, and many children effectively treated with these drugs still manifest a higher level of some behavioral problems than children without ADHD or other behavioral disturbances. Although stimulants have been shown to remain effective over many years, long-term benefits remain to be established.

Binge-Eating Disorder

Some amphetamines (e.g., lisdexamfetamine) are used in the treatment of binge-eating disorder. Controlled studies have demonstrated efficacy of lisdexamfetamine in reducing the mean number of binge days per week compared with placebo in adults with moderate to severe binge-eating disorder. For additional information on the treatment of binge-eating disorder, see Uses: Binge-Eating Disorder, in Lisdexamfetamine Dimesylate.

Exogenous Obesity

Amphetamines also have been used as adjuncts to caloric restriction and behavioral modification in the short-term treatment of exogenous obesity. Amphetamine sulfate as a single-ingredient preparation is used for the treatment of exogenous obesity as a short-term (i.e., a few weeks) adjunct in a regimen of weight reduction based on caloric restriction in patients refractory to alternative therapy (e.g., repeated diets, group programs, other drugs). The anorexigenic effect of sympathomimetic compounds used in the treatment of obesity appears to be temporary, seldom lasting more than a few weeks, and tolerance may occur. To help bring about and maintain loss of weight, the patient must be taught to curtail overeating and to consume a suitable diet. Prolonged administration of amphetamines is not recommended; however, obesity usually is a chronic disease, and short-term or intermittent therapy with anorexigenic drugs is unlikely to maintain a long-term benefit and is not recommended. Other anorexigenic agents (e.g., amphetamine congeners such as phentermine) with better safety profiles, including reduced potentials for misuse and abuse, generally are preferred to prototype amphetamines for the management of obesity. In the past, it was suggested that combined^{† [off-label]} therapy with fenfluramine (an amphetamine congener that stimulates release of serotonin [ 5-HT] at synapses and selectively inhibits the reuptake of serotonin at the presynaptic serotonergic nerve endings resulting in increased postsynaptic concentrations of serotonin in the CNS) and phentermine (an amphetamine congener that inhibits uptake of norepinephrine and dopamine) may provide complementary anorexigenic effects; therefore, such combined^{† [off-label]} therapy had been used widely in the 1990s in the management of obesity. However, because accumulated data on adverse effects associated with the drugs, fenfluramine hydrochloride (Pondimin) and its dextrorotatory isomer dexfenfluramine hydrochloride (Redux) were withdrawn from the US market in 1997. cauts">(See Cautions.)

Misuse and Abuse

Misuse and abuse of amphetamines, especially methamphetamine, for CNS stimulatory effects have experienced a resurgence. In large part, this resurgence has resulted from the relative ease with which methamphetamine can be synthesized clandestinely from readily available chemicals such as ephedrine or pseudoephedrine. chron-tox">(See Chronic Toxicity.) Recent restrictions (including enactment of the Comprehensive Methamphetamine Control Act of 1996, the Methamphetamine Anti-Proliferation Act [MAPA] of 2000, and the Combat Methamphetamine Epidemic Act of 2005) on the availability of these compounds are hoped to reverse this resurgence in misuse and abuse. For a more detailed discussion on methamphetamine abuse, see Uses: Misuse and Abuse, in Pseudoephedrine 12:12.12.

Amphetamines General Statement Dosage and Administration

Administration

Amphetamines are administered orally. When used in the treatment of narcolepsy or attention-deficit/hyperactivity disorder, the initial dose is given in the morning or on awakening. When used in the treatment of binge-eating disorder, the daily dose should be given in the morning. Because of the potential for insomnia, when amphetamines are administered in divided doses, late evening doses should be avoided. When used as an anorexigenic, the dose is usually given 30–60 minutes before meals.

Dosage

Since the effective dose varies considerably from patient to patient, initial doses of amphetamines should be small and dosage may be increased gradually as necessary. Amphetamines exhibit tachyphylaxis and dosage must be governed accordingly. In general, relatively smaller doses of dextroamphetamine salts may be given since dextroamphetamine possesses a stronger central action than does amphetamine.

Cautions for Amphetamines General Statement

Abuse Potential

CNS stimulants (e.g., amphetamines) have a high potential for abuse and dependence. The risk of abuse should be assessed prior to initiation of amphetamine therapy and patients should be monitored for signs of abuse and dependence during therapy.

Valvulopathy and Pulmonary Hypertension

Temporal association between use of fenfluramine (Pondimin) or dexfenfluramine (Redux) and the development of unusual mitral, aortic, tricuspid, and/or pulmonary valvular (usually multivalvular) and echocardiographic abnormalities (that sometimes occurred concomitantly with pulmonary hypertension, occasionally required open heart surgery, and rarely were fatal) resulted in the withdrawal of these anorexigenic agents from the US market in 1997. While such information was based on limited clinical data that were difficult to evaluate fully, the manufacturer of fenfluramine and dexfenfluramine decided that it was prudent to withdraw these drugs from the market. Because of pharmacologic differences between these drugs and prototypical amphetamines, the importance of these findings to other anorexigenic agents currently is unclear.

The adverse effects associated with these drugs were based on postmarketing reports from the Mayo Clinic and other health-care facilities about heart valve disease occurring in patients who were receiving combined therapy with fenfluramine and phentermine for the management of obesity. As a result of these initial reports of valvulopathy, prior to the withdrawal from the market, the manufacturer had added a boxed warning to the labeling of fenfluramine and dexfenfluramine concerning heart valve disease reported with use of these drugs. Subsequently, an additional 28 cases of cardiac valvulopathy were reported to FDA, involving patients who had received phentermine in combination with fenfluramine or with dexfenfluramine or who had received monotherapy with dexfenfluramine or fenfluramine. Report of these additional cases coincided with final journal publication (N Engl J Med, August 28, 1997) of the earlier Mayo Clinic report and prompted FDA to issue an updated, stronger warning about the potential risks of combined fenfluramine and phentermine therapy or monotherapy with dexfenfluramine; the warning summarized these and other US cases that then totaled 82. At the time, FDA warned clinicians who chose to continue prescribing these drugs for obesity to limit such prescription to patients with substantial obesity.

Cardiovalvular Abnormalities

Reports of abnormal heart valve findings, including echocardiographic features, dyspnea, chest pain, syncope, lower extremity edema, and/or new heart murmurs continued to accumulate during September 1997, and preliminary analysis by FDA of pooled data from several medical centers revealed abnormal echocardiographic findings in about 32% of 291 evaluated asymptomatic patients receiving fenfluramine or dexfenfluramine for up to 24 months, usually in combination with phentermine. Preliminary data suggest that the incidence of heart valve abnormalities may be higher in patients exposed to the anorexigenic agents for 6 months or longer when compared with those receiving the drugs for less than 6 months. In the pooled analysis, evidence of mild or more severe aortic regurgitation was present in 80 of the patients and that of moderate or more severe mitral regurgitation was present in 23 patients; aortic valve abnormalities of this severity reportedly are uncommon in the general population, occurring in about 5% of those not receiving these stimulants (placebo recipients) and in only about 1–2% of individuals younger than 50 years of age. While this analysis provided additional supportive evidence of a possible association between use of these anorexigenic agents and cardiac abnormalities, evaluation of the data has been difficult because of the absence of matched controls and pretreatment baseline data for the patients.

Subsequent data and analysis from several studies using matched controls have shown variable results when evaluating the estimated risk associated with the use of anorexigenic agents and abnormal heart valve findings. In one study, the prevalence of abnormal heart valve findings (as defined by FDA and the US Centers for Disease Control and Prevention [CDC] as at least mild aortic-valve or moderate mitral-valve insufficiency determined by an echocardiogram) was about 13, 25, or 26% in obese patients receiving dexfenfluramine (30 mg daily) alone, dexfenfluramine (30 mg daily) in combination with phentermine (30 mg daily), or fenfluramine (60–120 mg daily) in combination with phentermine (30 mg daily), respectively. Such valvulopathy reportedly only occurred in 1.3% of gender-, height-, age-, and weight-matched controls, thus indicating a substantially higher prevalence of abnormal heart valve findings in patients receiving the anorexigenic agents. Following modification of an ongoing randomized placebo-controlled study in obese patients originally designed to compare the efficacy and safety of conventional dexfenfluramine (15 mg twice daily) with those of extended-release dexfenfluramine (30 mg daily), valvulopathy (as defined by FDA) was reported in 6.9 or 4.5% of patients treated with dexfenfluramine (as conventional or extended-release preparations) or placebo, respectively, for a median of 2.5 months (the original study was terminated early) indicating an absolute difference of 2.4% between patients treated with the drug or placebo. In addition, results of a population-based follow-up study in obese patients receiving dexfenfluramine, fenfluramine, or phentermine and those of gender-, age-, and weight-matched controls also indicate an association between the anorexigenic agents and abnormal heart valve findings. The incidence of valvulopathy was zero cases per 10,000 in matched historical controls or in those who received phentermine while incidence of valvulopathy was 7.1 (0.071%) and 35 (0.35%) cases per 10,000 in patients who received either drug (dexfenfluramine or fenfluramine) for less than 4 months and for 4 months or longer, respectively. Patients diagnosed with heart valve abnormalities in this study received 15–60 or 60–120 mg of dexfenfluramine or fenfluramine, respectively.

In the population-based study, heart valve abnormalities were identified from clinical and echocardiographic findings from an electronic medical records database, and the higher-than-expected prevalence of valvular regurgitation occurring among anorexigenic agent users at the end of the follow-up was 1–2 times lower than that reported in the studies using FDA criteria for valvulopathy. It was suggested that such discordance may reflect the insensitivity of clinical evaluation in general practice in detecting mild to moderate valvular regurgitation. In addition, the use of echocardiographic findings that meet FDA criteria for valvulopathy may identify patients before the heart-valve abnormalities are clinically apparent. However, in the echocardiographic studies using placebo controls, the incidence of valvulopathy was in the range observed in echocardiographic studies of population samples, suggesting that the FDA criteria are reasonably specific and were applied in a consistent manner in the mentioned studies. In addition, analysis of the mentioned data provides further supportive evidence of the possible association between use of fenfluramine monotherapy, dexfenfluramine monotherapy, and combination of fenfluramine or dexfenfluramine with phentermine (but not with phentermine monotherapy) and cardiac abnormalities, especially in patients receiving long-term or high-dose administration of the drugs. However, such association may be less common than that suggested by the preliminary findings by FDA of pooled data from several medical centers in which abnormal echocardiographic findings occurred in about 32% of 291 evaluated asymptomatic patients receiving fenfluramine or dexfenfluramine for up to 24 months, usually in combination with phentermine. Subsequent studies have estimated a lower prevalence of such drug-related valvulopathy according to FDA criteria and identified age, dose, and duration of drug exposure as risk factors for the development of this abnormality. Very limited data indicate that cardiac valve abnormalities may regress in some patients.

Diagnostic Measures for Valvulopathy and Associated Precautions

FDA and other experts recommend that patients who were receiving fenfluramine or dexfenfluramine therapy discontinue the drugs. While most patients could safely discontinue the drugs after such notification, gradual tapering of dosage (e.g., over 1–2 weeks) has been advisable in some patients; therefore, patients were advised to consult their clinician regarding specific instructions for discontinuing the drugs. In addition, because of the severity of these cardiac effects, the US Department of Health and Human Services (DHHS) issued in 1997 interim recommendations that were developed by FDA in conjunction with the CDC and the National Institutes of Health (NIH) (the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases) and in consultation with the American Heart Association (AHA), the American College of Cardiology (ACC), and the American Dental Association (ADA) for individuals who received fenfluramine or dexfenfluramine as monotherapy or in combination with other drugs (e.g., phentermine). These recommendations, based on data from patients who developed fenfluramine- or dexfenfluramine-associated heart valve disease, state that in order to determine whether heart valve abnormalities are present in individuals who were exposed to these drugs either alone or in combination therapy and to provide such patients with optimal care, a medical history and a cardiovascular examination should be performed in all patients who have received the anorexigenic drugs. In addition, an echocardiogram (ECHO) should be performed on all patients who received fenfluramine or dexfenfluramine either alone or in combination therapy for any period of time and who exhibit cardiopulmonary signs (e.g., new murmur) or symptoms (e.g., dyspnea) suggestive of heart valve disease. Echocardiographic examination also should be performed in patients in whom cardiac auscultation is not possible.

Patients with clinical and echocardiographic evidence of heart valve disease should undergo treatment and/or further testing based on the specific valve lesions. The DHHS also states that while the clinical importance of asymptomatic valvular regurgitation and the risk of developing bacterial endocarditis in such individuals is not known, clinicians should strongly consider performing an echocardiogram on all patients who have been exposed to the anorexigenic agents, regardless of whether they have developed signs and symptoms of heart valve disease, if they are about to undergo any invasive procedure for which anti-infective prophylaxis for the prevention of bacterial endocarditis is indicated by the current recommendations published by the AHA. In case of emergency procedures, when cardiac evaluation cannot be performed, empiric preventive antimicrobial therapy should be administered. Because of uncertainties about the described heart valve abnormalities (e.g., incidence of substantial heart valve abnormalities; which patients are at high or low risk for developing such abnormalities; whether such abnormalities are reversible upon discontinuance of the anorexigenic drugs; the optimal timing of follow-up echocardiograms to determine progression, regression, or stabilization of cardiac valve lesions), the DHHS states that clinicians should exercise their best judgment based on the individual patient’s history and clinical and cardiac status to determine the need for additional echocardiographic follow-up. The DHHS anticipates that within 1 year sufficient data will become available to make further recommendations about such acquired valvular disease. Clinicians should continue to report to FDA at 800-332-1088 those patients with heart valve disease who have been exposed to fenfluramine, dexfenfluramine, phentermine, or any combination of these drugs.

Other Considerations for Valvulopathy

FDA also issued an advisory to state boards of pharmacy alerting them to reports that a number of pharmacies in various parts of the country may have been extemporaneously compounding fenfluramine and dexfenfluramine preparations as a result of withdrawal of commercially manufactured products, and that the agency expected pharmacies to refrain from distributing such compounded preparations because of the serious health risks associated with use of these anorexigenics. As of mid-September 1997, recommendations concerning phentermine monotherapy for obesity were not affected by the recall and patients were not being advised to necessarily discontinue such therapy if indicated. However, manufacturers of the drug state that phentermine only should be used for short-term treatment (a few weeks) of exogenous obesity and the drug should not be used in combination with selective serotonin-reuptake inhibitor antidepressants (e.g., fluoxetine, sertraline, paroxetine, fluvoxamine) or monoamine oxidase [MAO] inhibitors). In addition, phentermine should not be used in combination with phendimetrazine tartrate since abnormal heart valve findings and primary pulmonary hypertension have been reported in some patients receiving phendimetrazine in combination with other anorexigenic agents (e.g., phentermine).

Mechanism of Cardiac Abnormalities

The mechanism of these anorexigenic agent-associated adverse cardiac effects has not been elucidated. However, it has been suggested that the cardiac abnormalities may be related to serotonergic alterations induced by the drugs. Additional evidence purportedly supporting such a serotonin hypothesis includes the histopathologic similarity (e.g., plaque-like encasement of leaflets, chordal structures with a “stuck-on” appearance, intact valve architecture) between the anorexigenic valvulopathy observed in several patients who underwent cardiac surgery and the diseased valves observed in patients with carcinoid syndrome or in ergot toxicity. Although pulmonary hypertension has been reported in women who were found to have valvular regurgitation following fenfluramine or dexfenfluramine use, reversibility of valvular abnormalities also has been reported in some patients and the clinical course following discontinuance of the drugs remains to be elucidated.

Pulmonary Hypertension

Pulmonary hypertension in the absence of documented valvulopathy also has been reported in patients receiving amphetamines and amphetamine congeners, including dexfenfluramine, fenfluramine, phendimetrazine, and/or phentermine. Further study is needed to identify the possible mechanisms of action and risk factors for developing such adverse effects. Animal evidence of serotonin depletion in the CNS with prolonged use of dexfenfluramine has raised additional unresolved concerns about the long-term safety of fenfluramine and dexfenfluramine.

Peripheral Vascular Effects

Stimulants are associated with peripheral vascular disorders (e.g., Raynaud’s phenomenon). Manifestations usually are intermittent and mild, but ulceration of the digits and/or breakdown of soft tissue may occur rarely. Peripheral vascular disorders have been reported during postmarketing experience in patients in all age groups receiving stimulants at therapeutic dosages and at various times throughout the treatment course. Manifestations generally improve following dosage reduction or drug discontinuance. Careful observation for digital changes is warranted during therapy with stimulants, and further clinical evaluation (e.g., referral to a rheumatologist) may be appropriate for certain patients.

Serotonin Syndrome

Potentially life-threatening serotonin syndrome may occur when amphetamines are used concomitantly with other drugs that affect serotonergic neurotransmission, including MAO inhibitors, selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, 5-hydroxytryptamine (5-HT) type 1 receptor agonists (“triptans”), buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John’s wort (Hypericum perforatum). Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular aberrations, seizures, and/or GI symptoms.

Serotonin syndrome also may occur when amphetamines and inhibitors of cytochrome P-450 (CYP) isoenzyme 2D6 are used concomitantly. Amphetamines and amphetamine derivatives are known to be metabolized to some degree by CYP2D6 and may show mild inhibition of CYP2D6 metabolism. The potential for a pharmacokinetic interaction exists, since such concomitant administration may increase amphetamine exposure, and thereby increase the risk of serotonin syndrome. For further information on serotonin syndrome, including manifestations and management, see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions, in Lisdexamfetamine Dimesylate 28:20.04.

Other Adverse Effects

Adverse effects of amphetamines may include nervousness, insomnia, irritability, talkativeness, changes in libido, frequent or prolonged erections, dizziness, headaches, increased motor activity, chilliness, pallor or flushing, blurred vision, mydriasis, diplopia, difficulty with visual accommodation, and hyperexcitability. Exacerbation of motor or phonic tics, Tourette’s syndrome, dyskinesia, dermatillomania, seizures, euphoria, dysphoria, emotional lability, impotence, alopecia, eosinophilic hepatitis, and rhabdomyolysis have been reported in patients receiving amphetamines. Psychotic episodes have occurred rarely in patients receiving amphetamines at recommended dosages. Psychologic disturbances have occurred in patients receiving anorexigenic agents combined with dietary restrictions. Paradoxical, increased depression or agitation in depressed patients receiving the drug are indications for discontinuing amphetamine drugs. Hypertension or hypotension, tachycardia, palpitation, or cardiac arrhythmias may occur in some patients. Cardiomyopathy, usually manifested as ventricular hypertrophy and/or congestive heart failure, has occurred in patients receiving amphetamines chronically (e.g., chronic abusers) and is potentially fatal; the cardiomyopathy is similar to adrenergic cardiomyopathies (e.g., that associated with pheochromocytoma). Sudden death, myocardial infarction (MI), and stroke have been reported in patients receiving amphetamines. GI disturbances consisting of nausea, vomiting, abdominal cramps, diarrhea or constipation, dryness of the mouth, bruxism, anorexia, weight loss, and dysgeusia (e.g., unpleasant or metallic taste) have also been reported. Dermatologic or hypersensitivity reactions (e.g., urticaria, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, anaphylaxis ) also have been reported. Tolerance to the drugs does occur.

Precautions and Contraindications

Psychiatric Precautions

Aggressive behavior and hostility frequently are observed in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and have been reported in patients receiving drug therapy for the disorder. Although a causal relationship to stimulants has not been established, patients beginning treatment for ADHD should be monitored for the onset or worsening of aggressive behavior or hostility.

Psychotic or manic symptoms (e.g., hallucinations, delusional thinking, mania) have been reported in children and adolescents without prior history of psychotic illness or mania who received usual dosages of stimulants. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.1% of patients receiving usual dosages of stimulants (i.e., amphetamine, methylphenidate) compared with 0% of those receiving placebo. If psychotic or manic symptoms occur during stimulant therapy, a causal relationship to stimulants should be considered, and discontinuance of therapy may be appropriate.

Amphetamines should be used with caution in the management of ADHD in patients with comorbid bipolar disorder because of the potential for precipitation of mixed or manic episodes in such patients. Prior to initiating amphetamine therapy, patients should be carefully screened to determine if they are at risk for bipolar disorder or for developing a manic episode; such screening should include a detailed psychiatric history (e.g., comorbid depressive symptoms or history of depressive symptoms; family history of suicide, bipolar disorder, or depression).

Stimulants may exacerbate symptoms of behavior disturbance and thought disorder (psychotomimetic effects) in psychotic patients, including those with schizophrenia, psychosis not otherwise specified, or manic episodes with psychosis.

Each time amphetamines are dispensed, a medication guide should be provided to the patient or caregiver, alerting them to the risks associated with stimulant therapy (e.g., adverse psychiatric effects, possible cardiovascular risks) and advising them of necessary precautions. precaut-contra-03">(See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.) Patients or caregivers should be instructed to inform clinicians of suicidal ideation or behaviors or any preexisting mental or psychiatric disorder. They also should be instructed to inform clinicians immediately if adverse psychiatric effects (e.g., hallucinations, delusional thinking, mania) occur during stimulant therapy.

The possibility of psychic dependence or addiction should be considered, particularly when amphetamines are administered to alcoholic patients or to those known to have been addicted to other drugs.

Abrupt withdrawal of an amphetamine following prolonged administration may unmask severe depression as well as the effects of chronic overactivity; paranoid and suicidal ideation, dysphoric mood (e.g., depression, irritability, anxiety), fatigue, insomnia or hypersomnia, psychomotor agitation, agoraphobia and disturbed sleep also may occur. Therefore, patients should be carefully supervised during withdrawal of the drug; long-term follow-up may be required since some manifestations (e.g., depression) may persist for prolonged periods.

Cardiovascular Precautions

Stimulants cause modest increases in average blood pressure (i.e., by about 2–4 mm Hg) and heart rate (i.e., by about 3–6 bpm); larger increases may occur in some patients. Although modest increases would not be expected to have short-term sequelae, all patients should be monitored for larger changes in blood pressure and heart rate. Caution is advised in patients with underlying medical conditions that might be affected by increases in blood pressure or heart rate (e.g., hypertension, heart failure, recent MI, ventricular arrhythmia).

Serious cardiovascular events and sudden unexplained death have been associated with amphetamine abuse. In addition, although a causal relationship to stimulants has not been established, sudden unexplained death, stroke, and MI have been reported in adults receiving usual dosages of stimulants for the treatment of ADHD. Sudden unexplained death also has been reported in children and adolescents with underlying structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants. ped-precauts">(See Cautions: Pediatric Precautions.) A very small number of cases of sudden unexplained death have been reported in children without structural cardiac abnormalities receiving amphetamine combinations (fixed-combination preparations containing dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate); however, confounding factors were present in some of these incidents.

In February 2005, the Canadian drug regulatory agency suspended authorization for marketing of amphetamine combinations (Adderall XR) based on postmarketing reports of serious cardiovascular events (e.g., stroke) and sudden unexplained death in patients receiving the drug. However, in October 2005, following review of the safety data by an independent expert panel, the agency reversed its previous decision, thereby allowing the manufacturer to market the drug in Canada. This change was based on the agency’s acceptance of the panel’s recommendations, which included revision of the cautionary information in the Canadian product labeling and enhanced postmarketing surveillance of all stimulants used in the treatment of ADHD.

In May 2006, following review of safety data on stimulants by 2 advisory committees, FDA directed manufacturers of ADHD stimulant preparations to revise the US product labeling to include stronger wording regarding serious adverse cardiovascular effects. According to revised US product labeling, children, adolescents, and adults who are being considered for stimulant therapy should undergo a thorough medical history review (including evaluation for family history of sudden death or ventricular arrhythmia) and physical examination to detect the presence of cardiac disease, and should receive further cardiac evaluation (e.g., ECG, echocardiogram) if initial findings suggest such disease. Stimulants generally should not be used in children, adolescents, or adults with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac conditions. Patients who develop exertional chest pain, unexplained syncope, or other manifestations suggestive of cardiac disease during stimulant therapy should undergo prompt cardiac evaluation.

In addition to stronger wording in the revised US product labeling, FDA, in February 2007, directed manufacturers of ADHD stimulant preparations to develop written patient information (a medication guide) to alert patients to possible cardiovascular risks and risks of adverse psychiatric effects associated with these drugs and to advise patients of necessary precautions. precaut-contra-03">(See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.) Patients and caregivers should be instructed to inform clinicians of preexisting cardiac or cardiovascular disease. They also should be instructed to inform clinicians immediately if adverse cardiovascular effects (e.g., chest pain, shortness of breath, fainting) occur during stimulant therapy.

Following release of the medication guide and revised US product labeling for stimulant drugs, the AHA issued additional recommendations regarding screening for cardiac conditions, selection of appropriate candidates for stimulant therapy, and monitoring for treatment-emergent cardiac conditions. In a recent scientific statement, the AHA recommends that, in addition to undergoing a thorough medical history review and physical examination, all children and adolescents being considered for stimulant therapy obtain a baseline ECG regardless of whether findings suggestive of cardiac disease are present. The AHA also recommends that an ECG, a thorough medical history review, and physical examination be obtained (if not already available) in children and adolescents currently receiving stimulants. In patients with a baseline ECG who currently are receiving stimulant therapy, the AHA states that a repeat ECG may be beneficial after the patient reaches 12 years of age or if symptoms suggestive of cardiac disease or a change in family history is reported. While sharing the AHA’s goal of detecting silent but clinically important cardiac conditions, the American Academy of Pediatrics (AAP) does not support AHA’s recommendation to obtain a baseline ECG before initiating stimulant therapy, noting that: (1) the incidence of sudden cardiac death in children and adolescents receiving therapy for ADHD is not higher than that in the general population; (2) there are no data indicating that stimulant therapy increases the risk of sudden cardiac death in patients with preexisting cardiac conditions; (3) there are no data indicating that routine ECG screening before initiation of therapy prevents sudden death; and (4) there is no cost-effectiveness analysis to justify ECG screening or special evaluations by pediatric cardiologists.

Results of one retrospective, case-control epidemiologic study showed that there may be an association between use of stimulant medications (amphetamine, dextroamphetamine, methamphetamine, methylphenidate, or their derivatives) and sudden unexplained death in healthy children and adolescents. ped-precauts">(See Cautions: Pediatric Precautions.) Because of postmarketing reports and the results of this and other epidemiologic studies, FDA collaborated with the Agency for Healthcare Research and Quality (AHRQ) to sponsor 3 large, related, retrospective cohort studies using data from several health care claims databases to evaluate possible associations between ADHD drug use (stimulants, atomoxetine, and pemoline [no longer commercially available in the US]) and the following serious cardiovascular events: MI, stroke, and sudden cardiac death in children and young adults 2–24 years of age; MI and sudden cardiac death in adults 25–64 years of age; and stroke and the composite end point of stroke, MI, and sudden cardiac death in the same group of adults. None of the 3 studies (results of which were released in 2017) showed an association between serious cardiovascular events and current use of ADHD drugs, as compared with nonuse or as compared with former or remote use, although small increases in cardiovascular risk could not be excluded. The study in children and young adults included data for approximately 1.2 million patients and approximately 2.6 million patient-years of follow-up, including approximately 370,000 patient-years of current ADHD drug use, and found only 7 serious cardiovascular events (4 strokes, 3 sudden deaths) in current users of the drugs. The analyses in adults included data for approximately 440,000 patients, including approximately 150,000 current users of ADHD drugs; for the composite outcome of stroke, MI, and sudden cardiac death, there were approximately 107,000 patient-years of ADHD drug exposure and 234 such cardiovascular events in current users.

While the revised US product labeling states that stimulants generally should not be used in children, adolescents, or adults with known serious cardiac conditions, the AHA states that use of stimulants may be considered in children and adolescents with congenital heart disease that is not repaired, repaired but without current hemodynamic or arrhythmic concerns, or considered to be stable. In addition, the AHA states that, after considering or using other methods of treatment for ADHD, it is reasonable to use stimulants with caution and with careful monitoring in children and adolescents with cardiac conditions associated with sudden cardiac death (e.g., long- or short-QT syndrome, hypertrophic cardiomyopathy, Marfan syndrome, Wolff-Parkinson-White syndrome); a history of arrhythmias requiring resuscitation, cardioversion, defibrillation, or overdrive pacing; previous aborted sudden cardiac death; elevated heart rate and blood pressure; prolonged QT_c interval; or other clinically important arrhythmia not treated or controlled. However, if any of the aforementioned conditions or arrhythmias are diagnosed during stimulant therapy, the AHA recommends considering discontinuance of stimulant therapy until further testing and treatment can be obtained. If arrhythmias are treated and controlled, stimulant therapy may be reinitiated as appropriate.

Other Precautions and Contraindications

The manufacturer’s patient information (medication guide) should be provided to the patient or caregiver each time amphetamines are dispensed, and the clinician should discuss and answer questions about its contents (e.g., benefits and risks of stimulant therapy, appropriate use) as needed. The patient or caregiver should be instructed to read and understand the contents of the medication guide before initiating therapy and each time the prescription is refilled.

Patients or caregivers should be instructed to inform clinicians of preexisting illnesses or conditions (e.g., cardiac or cardiovascular disease, thyroid disease, glaucoma, suicidal ideation or behaviors, mental or psychiatric disorder, seizures, circulation problems in fingers and toes).

Patients should be warned that amphetamines may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Narcoleptic patients with severe sleepiness as a manifestation of their disease should be advised to avoid potentially dangerous activities at home and work and should not operate a motor vehicle until sleepiness is appropriately controlled by stimulant drug therapy.

Amphetamines should be administered with caution, if at all, to patients with hyperexcitability states or to those receiving drugs which may produce this effect. Amphetamines should also be used with caution in geriatric, debilitated, or asthenic patients or in those with psychopathic personalities or history of suicidal or homicidal tendencies.

Visual disturbances (difficulty with accommodation, blurred vision) have been reported in patients receiving stimulants.

There is some clinical evidence that stimulants may lower the seizure threshold in patients with a history of seizures, in those with prior EEG abnormalities but no history of seizures, and, very rarely, in those without a history of seizures and no prior evidence of EEG abnormalities. If seizures occur, stimulants should be discontinued.

Therapy with CNS stimulants may be associated with at least a temporary suppression of growth in children. ped-precauts">(See Cautions: Pediatric Precautions.)

Large doses of amphetamines may cause fatigue, mental depression, an increase in blood pressure, cyanosis and respiratory failure, disorientation, hallucinations, seizures, and coma.

Phentermine should be discontinued in any patient who develops new, unexplained symptoms of dyspnea, angina, syncope, or edema of the lower extremities.

Amphetamines are contraindicated in patients with hyperthyroidism, advanced arteriosclerosis, agitated states, moderate to severe hypertension, symptomatic cardiovascular disease, glaucoma, or a history of drug abuse, and in those with a previous history of hypersensitivity or idiosyncrasy to sympathomimetic amines. Although amphetamines generally should not be used in patients with a history of drug abuse, some experts state that this is not an absolute contraindication, provided the patient can be monitored more carefully than would otherwise be indicated. Neurologic and circulatory reactions have been reported in patients who have received sympathomimetic amines concomitantly with MAO inhibitors, and fatalities have occurred. Amphetamines are contraindicated during or within 14 days of administration of MAO inhibitors. The drugs should not be used to prevent hypotension in patients who have undergone general anesthesia with drugs (cyclopropane, halothane) that sensitize the heart to the arrhythmia-producing potential of sympathomimetic amines.

Pediatric Precautions

Amphetamines should not be used as anorexigenic agents in children younger than 12 years of age. Some manufacturers state that amphetamines should not be used in attention-deficit/hyperactivity disorder (ADHD) in children younger than 6 years of age, while others state that amphetamines should not be used in such disorder in children younger than 3 years of age. Lisdexamfetamine should not be used for the treatment of binge-eating disorder in pediatric patients younger than 18 years of age.

Aggressive behavior, hostility, and psychotic or manic symptoms (e.g., hallucinations, delusional thinking, mania) have been reported in children and adolescents receiving stimulants for the management of ADHD. precaut-contra-01">(See Psychiatric Precautions under Cautions: Precautions and Contraindications.)

Sudden death has been reported in children and adolescents with structural cardiac abnormalities or other serious cardiac conditions receiving usual dosages of stimulants. Although a causal relationship to stimulants has not been established, and some serious cardiac conditions are independently associated with an increased risk of sudden death, stimulants generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac conditions that may increase their vulnerability to the sympathomimetic effects of such drugs. Sudden unexplained death also has been reported in a small number of children without structural cardiac abnormalities receiving amphetamine combinations (fixed-combination preparations containing dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate); however, confounding factors were present in some of these incidents. Results of one retrospective, case-control epidemiologic study suggested a possible association between use of stimulant medications (amphetamine, dextroamphetamine, methamphetamine, methylphenidate, or their derivatives) and sudden unexplained death in healthy children and adolescents. precaut-contra-02">(See Cardiovascular Precautions under Cautions: Precautions and Contraindications.)

Prolonged administration of CNS stimulants to children with ADHD has been reported to cause at least a temporary suppression of normal weight and/or height patterns in some patients. Results of an analysis of weight and height patterns in children 7–13 years of age suggested that treatment with methylphenidate for up to 3 years was associated with a temporary slowing in growth rate (on average, height gain was suppressed by about 2 cm and weight gain was suppressed by 2.7 kg over 3 years), without evidence of growth rebound during this period of development. Published data are inadequate to determine whether long-term use of amphetamines may cause a similar suppression of growth; however, because appetite suppression and weight loss are common with stimulant therapy, and there is no apparent difference in their occurrence between amphetamine (e.g., dextroamphetamine) or methylphenidate therapy in children, it is anticipated that amphetamines, like methylphenidate, also cause temporary growth suppression. Therefore, the manufacturers of stimulant preparations state that growth should be monitored during therapy with stimulants, and children who are not growing or gaining height or weight as expected may require temporary discontinuance of therapy. Although concerns about potential dose-related growth delays in children have been raised, a prospective follow-up study into adulthood found no significant impairment in height achieved. In general, studies of stimulants in children have found little or no decrease in expected height, with any decrease in growth early in treatment being compensated for later on. Although drug holidays during summers have been suggested to minimize weight loss and other potential adverse effects, there currently are no data from controlled studies establishing whether such holidays are beneficial or associated with risks.

CNS stimulants, including amphetamines, have been reported to exacerbate motor and vocal tics and Tourette’s disorder, and clinical evaluation for tics and Tourette’s disorder in children and their families should precede use of the drugs. About 15–30% of children with ADHD experience tics while receiving stimulants, but such tics usually are transient. About half of children with ADHD have underlying Tourette’s syndrome, and the effects of stimulants on tics are unpredictable; the presence or emergence of tics is not an absolute contraindication to stimulant therapy, and some evidence indicates that the incidence of tics is not increased with such therapy. In addition, clinical experience suggests that administration of amphetamines in psychotic children may exacerbate symptoms of behavior disturbance and thought disorder.

Pregnancy and Lactation

Pregnancy

Amphetamines may cause fetal harm. Amphetamines should be used during pregnancy only if the potential benefits justify the possible risks to the fetus. During pregnancy, it is questionable whether potential benefits from amphetamines outweigh potential risks.

Amphetamines may stimulate uterine contractions in pregnant women increasing the risk of premature delivery. Infants born to women dependent on amphetamines have an increased risk of prematurity, low birthweight, and withdrawal symptoms (e.g., dysphoria, lassitude, feeding difficulties, irritability, agitation, excessive drowsiness).

Lactation

Amphetamines are distributed into milk in concentrations 2–8 times maternal blood concentrations. Large dosages of dextroamphetamine may interfere with milk production, especially in women whose lactation is not well established. Because of the potential for serious adverse effects in nursing infants, breast-feeding is not recommended during amphetamine therapy.

Acute Toxicity

Pathogenesis

Despite the high toxicity and wide distribution of amphetamines, death occurs rarely following acute overdosage. There is a relatively large margin of safety between the amount of drug incorporated in a unit therapeutic dose and the lethal dose. In adults, 120 mg of amphetamine has caused death, but in one patient 200 mg produced only mild signs of peripheral sympathomimetic activity. Death usually is preceded by seizures and coma and usually results from cardiovascular collapse or from seizures.

Manifestations

Overdose of an amphetamine may be manifested initially by cardiovascular symptoms including flushing or pallor, palpitation, tachypnea, tremor, labile pulse rate and blood pressure (hypertension or hypotension), cardiac arrhythmias (e.g., extrasystoles), heart block, circulatory collapse, and chest pain. Toxic doses of phenylisopropylamines produce marked and photosensitive mydriasis, profuse perspiration, and polypnea. Elevated environmental temperature and other environmental factors such as crowding or aggregation markedly increase the acute toxicity of amphetamines in experimental animals. Although comparable clinical data in humans are lacking, hyperpyrexia has been noted as a frequent and prominent sign of acute human intoxication. Rhabdomyolysis also has been associated with acute overdosage of amphetamines, and hyperpyrexia and/or rhabdomyolysis can result in associated complications. Mental disturbances such as confusion, delirium, belligerence, or acute psychoses with disorientation, delusions, and hallucinations may occur. Overdosage may be characterized by restlessness, vivid visual and auditory hallucinations, panic state, suicidal or homicidal tendencies, paranoid ideation, combativeness, loosening of associations, or changes in affect occurring in association with a clear sensorium. Fatigue and depression usually follow CNS stimulation. The psychotic syndrome may occur within 36–48 hours after ingestion of a single large dose of an amphetamine. In apparently hypersensitive individuals, psychosis may be produced by a single dose of 55–75 mg of dextroamphetamine. Overdose of an amphetamine also may be manifested by GI symptoms including nausea, vomiting, diarrhea, and abdominal cramps. After a single large oral dose, amphetamine is slowly excreted over a period of 5–7 days, suggesting the possibility that cumulative effects may occur with repeated administration of the drug. If the patient does not receive additional doses of the drug, the psychosis usually clears within about 1 week.

The toxic effects are more variable in children than in adults and acute toxicity in children has occurred over a wide range of dosage. In a 2-year-old child, 40–50 mg of dextroamphetamine produced toxicity even when 60–75 mg of phenobarbital were ingested at the same time. Another child, slightly older than 2 years of age, survived 115 mg of dextroamphetamine. Overdosage of amphetamines in children may be manifested by constant twisting and turning, purposeless movement, mumbling, and hyperirritability. Children may be in a tremulous state for up to 12 hours following ingestion of an overdosage of an amphetamine without having a seizure. In acute poisoning in a child, external stimuli precipitate increased hyperactivity. Overdosage in children may also produce confusion, delirium, hallucinations, carphology, panic state, and other acute psychotic syndromes. Children also may exhibit self-destructive behavior, such as head banging and mutilation of digits by biting, and violent, purposeless movements.

Treatment

There is no specific antidote for amphetamine overdosage. Treatment of overdosage is symptomatic and includes administration of sedative drugs, preferably short-acting barbiturates, and isolation of the patient to avoid possible external stimuli. In the treatment of overdosage, general physiologic supportive measures should be immediately undertaken. Standard treatment for shock should be administered if necessary. Absorption of the drug should be delayed by use of a tourniquet and ice pack following injection or by emesis or gastric lavage if the drug has been ingested, and excretion may be hastened by acidification of the urine with ammonium chloride. Hypothermic measures may be used if necessary and if intracranial pressure rises, measures to combat cerebral edema and congestion should be used.

Chronic Toxicity

At normal dosage levels, administration of an amphetamine may produce tolerance within a few weeks. Prolonged use of an amphetamine may lead to habituation and possibly physical or psychic dependence. Amphetamines are abused by some users for their central exciting action and since these drugs temporarily lessen fatigue, they are frequently abused by persons in occupations requiring extremes of endurance, such as students, athletes, and drivers of motor vehicles. Some emotionally unstable individuals come to depend on the pleasant mental stimulation the drugs offer.

The symptoms of chronic abuse of amphetamines are similar to those of cocaine and consist of emotional lability, loss of appetite, somnolence, mental impairment, occupational deterioration, and a tendency to withdraw from social contacts. Chronic users of amphetamines exhibit continuous chewing or teeth-grinding movements, with rubbing of the tongue along the inside of the lower lip, frequently resulting in trauma and ulcers of the tongue and lip, and other choreoathetoid manifestations. Amphetamines are frequently used concurrently or alternately with alcohol or barbiturates. The average daily dose ingested by an abuser is equivalent to about 1–2 g of amphetamine. Prolonged use of high doses can elicit a syndrome that presents all characteristics of paranoid schizophrenia, including auditory and visual hallucinations and paranoid ideation. Rarely, prolonged use of amphetamine has caused aplastic anemia and fatal pancytopenia.

Because of the relative ease with which methamphetamine (“speed,” “crystal,” “crank,” “go,” “ice”) can be synthesized clandestinely from commonly available chemicals such as ephedrine, pseudoephedrine, or phenylpropanolamine (see Uses: Misuse and Abuse in the respective monographs on these drugs in 12:12.12), misuse and abuse of amphetamines have experienced a resurgence in the US. Currently, methamphetamine is the most widely illegally manufactured, distributed, and abused amphetamine in the US, with an estimated 4 million Americans having abused the drug at least once. In addition, morbidity and mortality from methamphetamine abuse have increased substantially in the US since 1990, particularly in the West but also in the South and Midwest. From 1991 to 1994, the number of methamphetamine-related deaths reported by medical examiners in the US about tripled, with the number increasing by 850, 238, 144, and 113% in Phoenix, San Diego, San Francisco, and Los Angeles, respectively. Most decedents were 26–44 years of age, male, and white, and nearly all deaths involved methamphetamine taken in combination with at least one other drug, principally alcohol, heroin, or cocaine. Methamphetamine-related hospital emergency room visits more than tripled during this period, especially in Phoenix, Denver, Minneapolis/St. Paul, and Seattle but also in cities in the South and Midwest (e.g., Atlanta, St. Louis, Dallas). In some areas, the popularity of methamphetamine abuse exceeds that of cocaine. Contributing to the resurgence in abuse of methamphetamine are ready availability in many cities, relatively inexpensive cost, more immediate and sustained effect compared with cocaine or “crack” cocaine, and multiple routes of administration (injection, “snorting,” ingestion, and smoking). In addition to the potential adverse effects directly attributable to methamphetamine, abuse of the drug also may be associated with indirect risks such as the development of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS); in all regions of the US, sexually active bisexual and homosexual men were more likely than heterosexual men to report amphetamines as the principal parenteral drugs of abuse. Because of the regional variability in methamphetamine abuse in the US, local drug-abuse patterns should be evaluated for planning preventive and treatment services.

The addiction potential of amphetamines is subject to controversy. Most authorities agree that long-term therapy with amphetamine or one of its isomers is unlikely to produce addiction and that habituation or psychic dependence is caused by psychological factors which lead to abuse of the drug and not by any pharmacologic action. In one study, however, abrupt withdrawal of large doses of amphetamine caused a consistent increase in the percentage of the rhombencephalic phase of the EEG pattern during sleep. The percentage returns to normal levels when amphetamine is readministered and rises again when the drug is withheld. This phenomenon meets the usual criteria for a withdrawal symptom but does not alter the fact that abrupt discontinuation of sympathomimetic amines does not cause major physiological changes that would necessitate gradual reduction of the medication.

Pharmacology

The pharmacologic actions of amphetamines are qualitatively similar to those of ephedrine and include CNS and respiratory stimulation and sympathomimetic activity including pressor response, mydriasis, bronchodilation, and contraction of the urinary bladder sphincter. The effect of amphetamines on the motility of the GI tract is variable and unpredictable. On a weight basis, dextroamphetamine has a stronger CNS action and a lesser activity on the peripheral nervous system than does the racemic amphetamine. The CNS stimulating effect of dextroamphetamine is approximately twice that of amphetamine and about three or four times that of levamfetamine (no longer commercially available in the US). Levamfetamine is slightly more potent than dextroamphetamine in its cardiovascular effects. In healthy individuals, therapeutic doses of an amphetamine do not appreciably increase respiratory rate or minute volume, but when respiration is depressed by centrally acting drugs, an amphetamine stimulates respiration. The bronchodilating effect of amphetamines is less than that of ephedrine.

Amphetamines may superimpose psychic stimulation and excitability over fatigue, permitting a temporary increase in mental and physical activity. In healthy individuals, the drugs have not consistently facilitated improved mental performance and in some cases, nervousness produced by amphetamines is a distinct mental hazard. The most striking improvement caused by an amphetamine appears to occur when performance has been reduced by fatigue; such improvement may be due to alteration of unfavorable attitudes toward the task. Psychic stimulation produced by amphetamines is usually followed by depression and fatigue. Psychic effects depend on dose, mental state, and personality of the patient.

Theories of dysfunction in attention-deficit/hyperactivity disorder (ADHD) focus on the prefrontal cortex, which controls many executive functions (e.g., planning, impulse control). Stimulants have putative effects on central dopamine and norepinephrine pathways that are crucial in frontal lobe function. Stimulants act in the striatum by binding to the dopamine transporter, thus increasing synaptic dopamine. This effect may enhance functioning of executive control processes in the prefrontal cortex, ameliorating deficits in inhibitory control and working memory.

Amphetamines apparently produce an anorexigenic effect, leading to loss of weight. The mechanism of action of amphetamines on appetite suppression has not been elucidated. No primary effect on appetite has been demonstrated in humans and it has been postulated that anorexigenic effects of amphetamines are secondary to increased sympathetic activity resulting from amphetamine-induced release of norepinephrine and dopamine. In addition, amphetamines may cause a loss of acuity of smell and taste, which may contribute to the anorexigenic effect of the drugs. Amphetamines have little or no effect on the basal metabolic rate or on nitrogen excretion.

The anorexigenic effect of fenfluramine (no longer commercially available in the US) and dexfenfluramine (no longer commercially available in the US), amphetamine congeners, may have been associated with a different mechanism than those associated with amphetamines since the drugs appeared to stimulate release of serotonin (5-HT) at synapses and selectively inhibit the reuptake of serotonin at the presynaptic serotonergic nerve endings, which may have resulted in increased postsynaptic concentrations of serotonin in the CNS. In the past, it has been suggested that combined therapy with fenfluramine and phentermine (an amphetamine congener that inhibits uptake of norepinephrine and dopamine) may provide complementary anorexigenic effects; therefore, such combined therapy has been used in the management of obesity. However, because of accumulated data on adverse effects associated with the drugs, fenfluramine hydrochloride (Pondimin) and its dextrorotatory isomer dexfenfluramine hydrochloride (Redux) were withdrawn from the US market in 1997. cauts">(See Cautions.)

Amphetamines General Statement Pharmacokinetics

Amphetamines are readily absorbed from the GI tract and effects persist for 4–24 hours. Amphetamines are distributed into most body tissues with high concentrations occurring in the brain and CSF.

Amphetamine appears in the urine within about 3 hours following oral administration. Urinary excretion of the amphetamines is pH-dependent and excretion is enhanced in acidic urine. Following oral administration of racemic amphetamine to humans, approximately equal amounts of both isomers were excreted during the first 12 hours; after the first 12 hours, a continually decreasing proportion of the d-isomer was excreted. Following oral administration of a 70-mg radiolabeled dose of lisdexamfetamine (a prodrug of dextroamphetamine), 96% of the dose was recovered in the urine; of the recovered radioactivity, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to the parent drug. Dextroamphetamine and levamfetamine (no longer commercially available in the US) appear to have different metabolic fates, but the relationship between the fate of the drugs and their pharmacologic activity has not been determined. There are some data to indicate stereospecific metabolism of amphetamine and its isomers, but stereospecific urinary excretion appears unlikely.

Chemistry

Amphetamine is d,l-α-methylphenethylamine, an adrenergic agent of the phenylisopropylamine type. The levo- and dextroisomers, racemic amphetamine, and the salts of the isomers and of racemic amphetamine are used in medical practice. Amphetamine is a noncatechol, sympathomimetic amine and has a greater CNS stimulant activity than epinephrine and other catecholamines. Lisdexamfetamine dimesylate is a prodrug and has little, if any, pharmacologic activity until converted to dextroamphetamine in blood mainly via hydrolytic activity of erythrocytes.

Inactivation of sympathomimetic noncatecholamines largely depends on breakdown by monoamine oxidase and since substitution of an alkyl group for hydrogen on the α-carbon atom blocks enzymatic inactivation of the amino group, the duration of action of noncatecholamines (but not of catecholamines, which are inactivated largely by a different mechanism) is prolonged by α-substitution. The absence of a hydroxyl group on the aromatic ring of amphetamine reduces inactivation of the drug in the GI tract and the amphetamines are active following oral administration.

Amphetamines are subject to control under the Federal Controlled Substances Act of 1970.

Related Monographs

For further information on the chemistry, pharmacology, pharmacokinetics, uses, cautions, drug interactions, and dosage and administration of amphetamines, see the individual monographs in 28:20.04.

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