VA Class:CN801

AHFS Class:

• Amphetamines 28:20.04

Associated Monographs

• Amphetamine

• Benzphetamine

• Dextroamphetamine

• Lisdexamfetamine Dimesylate

• Methamphetamine

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

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.484 In addition, certain amphetamines are used as adjuncts to caloric restriction and behavioral modification in the short-term treatment of exogenous obesity.486 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.324,333,334,470,471,472 Amphetamines, particularly methamphetamine, have been misused and abused for their CNS stimulatory effects.337

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.448 However, because most clinical trials have involved small numbers of patients, the risk-to-benefit remains to be further established.448

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).448

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.448

Tolerance to the clinical effects may develop with long-term therapy, particularly at high dosages.448

Narcolepsy rarely occurs in children younger than 12 years of age,486 and the relative safety and efficacy of various stimulant drugs in this age group remains to be elucidated.445,447,448 Although amphetamines can be used for narcolepsy occurring in children,445,447,448,486 methylphenidate appears to be used most commonly based principally on extensive experience with the drug in pediatric patients with ADHD.448

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.422,423,424,425,426,427,428,429,434,435,436,437,438 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,438,439 and the choice of stimulant therapy should be individualized.440,441,438 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).437,438 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.452,453

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.438,439,440,441,442,443,444 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.438 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.438,439 Although stimulants have been shown to remain effective over many years, long-term benefits remain to be established.423,439,438,440,442,443,444

Binge-Eating Disorder

Some amphetamines (e.g., lisdexamfetamine) are used in the treatment of binge-eating disorder.484 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.484 For additional information on the treatment of binge-eating disorder, see Uses: Binge-Eating Disorder, in Lisdexamfetamine Dimesylate 28:20.04.

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).486 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,324,333,334,470,471 and short-term or intermittent therapy with anorexigenic drugs is unlikely to maintain a long-term benefit and is not recommended.324,333,334,470,471 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.318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,471,472 In the past, it was suggested that combined† therapy with fenfluramine (an amphetamine congener that stimulates release of serotonin [ 5-HT]321,322,323 at synapses318 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† 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 1997.352,353,354,373,411 (See Cautions.)

Misuse and Abuse

Misuse and abuse of amphetamines, especially methamphetamine, for CNS stimulatory effects have experienced a resurgence.337 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.337,338,339,340,341,342,343,344,345,346,347,403 (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)460 on the availability of these compounds are hoped to reverse this resurgence in misuse and abuse.337,348,349,403,457,458 For a more detailed discussion on methamphetamine abuse, see Uses: Misuse and Abuse, in Pseudoephedrine 12:12.12.

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.445,446,459,484,486 When used in the treatment of binge-eating disorder, the daily dose should be given in the morning.484 Because of the potential for insomnia, when amphetamines are administered in divided doses, late evening doses should be avoided.445,459 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.

Abuse Potential

CNS stimulants (e.g., amphetamines) have a high potential for abuse and dependence.484,486 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.484

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)352,353,356,360,363,365,366,367,368,369,370,371,372,374,386,388,393,394,395,396,418 resulted in the withdrawal of these anorexigenic agents from the US market in 1997.352,353,354,373,399 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.352,353,373,395,399 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.352,353,354,356,360,363,365,366,367,368,369,370,371,372,397,418 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.352,357,358,362 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.352,353,354,374 Report of these additional cases374 coincided with final journal publication ( N Engl J Med , August 28, 1997) of the earlier Mayo Clinic report360 and prompted FDA to issue an updated, stronger warning about the potential risks of combined fenfluramine and phentermine therapy or monotherapy with dexfenfluramine;358 the warning summarized these and other US cases that then totaled 82.358,360,374,375 At the time, FDA warned clinicians who chose to continue prescribing these drugs for obesity to limit such prescription to patients with substantial obesity.358

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 1997,352,353,386 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.352,353,354,386,388,391,399,401 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.386 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;352,353,354 aortic valve abnormalities of this severity reportedly are uncommon in the general population, occurring in about 5%406 of those not receiving these stimulants (placebo recipients) and in only about 1-2% of individuals younger than 50 years of age.404 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.352,396

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.404,405,406,407 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.404,407,408 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.404,407,408 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.406,407,408 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.405,407 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.405,407,408 Patients diagnosed with heart valve abnormalities in this study received 15-60 or 60-120 mg of dexfenfluramine or fenfluramine, respectively.405

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.404,405,406,407,408 It was suggested that such discordance may reflect the insensitivity of clinical evaluation in general practice in detecting mild to moderate valvular regurgitation.407 In addition, the use of echocardiographic findings that meet FDA criteria for valvulopathy may identify patients before the heart-valve abnormalities are clinically apparent.407 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.407 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.407,408 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.352,353,354,386,388,391,399,401,408 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.487 Very limited data indicate that cardiac valve abnormalities may regress in some patients.408,409

Diagnostic Measures for Valvulopathy and Associated Precautions

FDA and other experts recommend that patients who were receiving fenfluramine or dexfenfluramine therapy discontinue the drugs.359,384 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;359 therefore, patients were advised to consult their clinician regarding specific instructions for discontinuing the drugs.359 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).384,385,386,400,402 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.384,385,386,398,399,400,401,402 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.384,386,398,399,400 Echocardiographic examination also should be performed in patients in whom cardiac auscultation is not possible.384

Patients with clinical and echocardiographic evidence of heart valve disease should undergo treatment and/or further testing based on the specific valve lesions.384,398 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.386,387,398,399,400,401,402 In case of emergency procedures, when cardiac evaluation cannot be performed, empiric preventive antimicrobial therapy should be administered.386 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.385,386,402 The DHHS anticipates that within 1 year sufficient data will become available to make further recommendations about such acquired valvular disease.386 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.385,386,396,401

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.383 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.359,395 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).392,393,395,397 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).417,419

Mechanism of Cardiac Abnormalities

The mechanism of these anorexigenic agent-associated adverse cardiac effects has not been elucidated.363,367,369,371,396,420,421 However, it has been suggested that the cardiac abnormalities may be related to serotonergic alterations induced by the drugs.360,367,369,371 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.356,371,388,389,390,396,404 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.356,364,371,388

Pulmonary Hypertension

Pulmonary hypertension in the absence of documented valvulopathy also has been reported in patients receiving amphetamines and amphetamine congeners, including dexfenfluramine,319,350,379,380 fenfluramine,355,361,371,382 phendimetrazine,417,419 and/or phentermine.371,392,393,394,395 Further study is needed to identify the possible mechanisms of action and risk factors for developing such adverse effects.367,369,371,386,399 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.376,377,378

Peripheral Vascular Effects

Stimulants are associated with peripheral vascular disorders (e.g., Raynaud's phenomenon).482,483,484,486 Manifestations usually are intermittent and mild, but ulceration of the digits and/or breakdown of soft tissue may occur rarely.482,483,484,486 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.482,483,484,486 Manifestations generally improve following dosage reduction or drug discontinuance.482,483,484,486 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.482,483,484,486

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) .482,483,484,486 Symptoms of serotonin syndrome may include mental status changes, autonomic instability, neuromuscular aberrations, seizures, and/or GI symptoms.482,483,484,486

Serotonin syndrome also may occur when amphetamines and inhibitors of cytochrome P-450 (CYP) isoenzyme 2D6 are used concomitantly.482,483,484,486 Amphetamines and amphetamine derivatives are known to be metabolized to some degree by CYP2D6 and may show mild inhibition of CYP2D6 metabolism.482,483,484,486 The potential for a pharmacokinetic interaction exists, since such concomitant administration may increase amphetamine exposure, and thereby increase the risk of serotonin syndrome.482,483,484,486 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,482,483,484,486 dizziness, headaches, increased motor activity, chilliness, pallor or flushing, blurred vision, mydriasis, diplopia,484 difficulty with visual accommodation,482,483,484,486 and hyperexcitability. Exacerbation of motor or phonic tics,445,446,459,463 Tourette's syndrome,445,446,459 dyskinesia,445,446,459,463 dermatillomania,482,483,484 seizures,445,446,463 euphoria,445,446,459 dysphoria,445,446,459,463 emotional lability,446 impotence,445,446,459,463 alopecia,482,483,484 eosinophilic hepatitis,484,485 and rhabdomyolysis482,483,484,486 have been reported in patients receiving amphetamines.445,446,459,463 Psychotic episodes have occurred rarely in patients receiving amphetamines at recommended dosages.445,446,459,463 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).300,301,302,303,304,305,307,308,309,310,463 Sudden death,445,446,463,475,476,477 myocardial infarction (MI),445,446,463 and stroke445,446,463 have been reported in patients receiving amphetamines.445,446,463 GI disturbances consisting of nausea, vomiting, abdominal cramps, diarrhea or constipation, dryness of the mouth, bruxism,483,484 anorexia, weight loss, and dysgeusia482,483,484,486 (e.g., unpleasant or metallic taste) have also been reported. Dermatologic or hypersensitivity reactions (e.g., urticaria,445,446,459,463 rash,445,446,463 Stevens-Johnson syndrome,445,446,463 toxic epidermal necrolysis,445,446,463 angioedema,445,446,463 anaphylaxis445,446,463 ) also have been reported.445,446,459,463 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.445,446,459 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.445,446,459

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.445,446,459,463 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.445,446,459,463 If psychotic or manic symptoms occur during stimulant therapy, a causal relationship to stimulants should be considered, and discontinuance of therapy may be appropriate.445,446,459,463

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.445,446,459,463 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).445,446,459,463,482,483,484,486

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.445,446,447,459,463

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.466 (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.467,468 They also should be instructed to inform clinicians immediately if adverse psychiatric effects (e.g., hallucinations, delusional thinking, mania) occur during stimulant therapy.467,468

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.445,446,459,463,486 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.445,446,459,463,486 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).445,446,459,486

Serious cardiovascular events and sudden unexplained death have been associated with amphetamine abuse.445,446,449,459 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.445,446,449,459,463 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.445,446,449,459,463 (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.449

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.449,451,473 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.454,455,456 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.454,455,456

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.461,462 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.445,446,459,463,475 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.445,446,449,459,463,464 Patients who develop exertional chest pain, unexplained syncope, or other manifestations suggestive of cardiac disease during stimulant therapy should undergo prompt cardiac evaluation.445,446,459,463

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.466 (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.467,468 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.467,468,475

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.473 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.473 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.473 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.473 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.474

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.475,476,477 (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 a MI and sudden cardiac death in adults 25-64 years of a and stroke and the composite end point of stroke, MI, and sudden cardiac death in the same group of adults.478,479,480,481 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.478,479,480,481 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.478,481 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.479,480

While the revised US product labeling states that stimulants generally should not be used in children, adolescents, or adults with known serious cardiac conditions,445,446,449,459,463,464 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.473 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.473 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.473 If arrhythmias are treated and controlled, stimulant therapy may be reinitiated as appropriate.473

Other Precautions and Contraindications

The manufacturer's patient information (medication guide) should be provided to the patient or caregiver each time amphetamines are dispensed,466,486 and the clinician should discuss and answer questions about its contents (e.g., benefits and risks of stimulant therapy, appropriate use) as needed.446,459 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.446,459,467,468,486

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).467,468,486

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.448

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.445,446,459,463,486

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.445,446,459,486 If seizures occur, stimulants should be discontinued.445,446,459,486

Therapy with CNS stimulants may be associated with at least a temporary suppression of growth in children.445,446,459,463,486 (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.393,420,421

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,447,463 some experts state that this is not an absolute contraindication, provided the patient can be monitored more carefully than would otherwise be indicated.447 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.486 Some manufacturers state that amphetamines should not be used in attention-deficit/hyperactivity disorder (ADHD) in children younger than 6 years of age,483,484 while others state that amphetamines should not be used in such disorder in children younger than 3 years of age.482,486 Lisdexamfetamine should not be used for the treatment of binge-eating disorder in pediatric patients younger than 18 years of age.484

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.446,459,463 (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.445,446,459,463 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.445,446,459,463 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.449 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.475,476,477 (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.445,446,459,463 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,438 it is anticipated that amphetamines, like methylphenidate, also cause temporary growth suppression.445,446,459,463 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.445,446,459,463 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.438 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.438 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.438

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.438 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.438 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.484 Amphetamines should be used during pregnancy only if the potential benefits justify the possible risks to the fetus.445,446,463 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.484 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).445,446,448,463,465,484

Lactation

Amphetamines are distributed into milk in concentrations 2-8 times maternal blood concentrations.318,448,465,484 Large dosages of dextroamphetamine may interfere with milk production, especially in women whose lactation is not well established.484 Because of the potential for serious adverse effects in nursing infants, breast-feeding is not recommended during amphetamine therapy.482,483,484

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,308,309,310,311 and hyperpyrexia308 and/or rhabdomyolysis308,311 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.312

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),337,338,339,340,341,342,343,344,345,346,347 misuse and abuse of amphetamines have experienced a resurgence in the US.337,338,339,340,341,342,343,344,345,346,347 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.337 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.337 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.337 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.337 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).337 In some areas, the popularity of methamphetamine abuse exceeds that of cocaine.337 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).337 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.337 Because of the regional variability in methamphetamine abuse in the US, local drug-abuse patterns should be evaluated for planning preventive and treatment services.337

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).447 Stimulants have putative effects on central dopamine and norepinephrine pathways that are crucial in frontal lobe function.447 Stimulants act in the striatum by binding to the dopamine transporter, thus increasing synaptic dopamine.447 This effect may enhance functioning of executive control processes in the prefrontal cortex, ameliorating deficits in inhibitory control and working memory.447

Amphetamines apparently produce an anorexigenic effect, leading to loss of weight. The mechanism of action of amphetamines on appetite suppression has not been elucidated.318 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.318 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)321,322,323 at synapses318 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.318,319 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.321,322,323 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 1997.352,353,354,373 (See Cautions.)

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.463 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.484

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.

Only references cited for selected revisions after 1984 are available electronically.

300. Cornaert P, Camblin J, Graux P et al. [Congestive cardiomyopathy in addiction to clobenzorex, an anorexigenic drug.] (French; with English abstract.) Arch Mal Coeur . 1986; 79:515-8.

301. Rajs J, Falconer B. Cardiac lesions in intravenous drug addicts. Forensic Sci Int . 1979; 13:193-209. [PubMed 456961]

302. Smith HJ, Roche AH, Jausch MF et al. Cardiomyopathy associated with amphetamine administration. Am Heart J . 1976; 91:792-7. [PubMed 132114]

303. Call TD, Hartneck J, Dickinson WA et al. Acute cardiomyopathy secondary to intravenous amphetamine abuse. Ann Intern Med . 1982; 97:559-60. [PubMed 7125413]

304. Ayres PR. Amphetamine cardiomyopathy. Ann Intern Med . 1983; 98:110. [PubMed 6848027]

305. Croft CH, Firth BG, Hillis LD. Propylhexedrine-induced left ventricular dysfunction. Ann Intern Med . 1982; 97:560-1. [PubMed 6127046]

306. Cameron J, Waugh L, Loadsman T et al. Possible association of pulmonary hypertension with an anorectic drug. Med J Aust . 1984; 140:595-7. [PubMed 6144037]

307. Morgan CD, Anderson RJ, Wilson JE III. Cardiopulmonary abnormalities in propylhexedrine (Benzedrex^®) shooters. Am Rev Respir Dis . 1980; 121:169.

308. The Upjohn Company. Didrex^® (benzphetamine hydrochloride) tablets prescribing information. In: Huff BB, ed. Physicians' desk reference. 43rd ed. Oradell, NJ: Medical Economics Company Inc; 1989:2161-2.

309. Smith Kline & French. Dexedrine^® (dextroamphetamine sulfate) Spansule^® capsules, tablets and elixir prescribing information. In: Huff BB, ed. Physicians' desk reference. 43rd ed. Oradell, NJ: Medical Economics Company Inc; 1989:2047-9.

310. Pennwalt Corporation. Biphetamine^® (amphetamine and dextroamphetamine resin complexes) capsules prescribing information. Rochester, NY; 1988 Jun.

311. Kendrick WC, Hull AR, Knochel JP. Rhabdomyolysis and shock after intravenous amphetamine administration. Ann Intern Med . 1977; 86:381-7. [PubMed 848798]

312. Espelin DE, Done AK. Amphetamine poisoning: effectiveness of chlorpromazine. N Engl J Med . 1968; 278:1361-5. [PubMed 5650165]

313. Lundh H, Tunving K. An extrapyramidal choreiform syndrome caused by amphetamine addiction. J Neurol Neurosurg Psychiatry . 1981; 44:728-30. [PubMed 7299411][PubMedCentral]

314. Briscoe JG, Curry SC, Gerkin RD et al. Pemoline-induced choreoathetosis and rhabdomyolysis. Med Toxicol Adverse Drug Exp . 1988; 3:72-6. [PubMed 3367787]

315. The United State pharmacopeia, 22nd rev, and the national formulary, 17th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1989(Suppl 3):2358-9.

316. The USP Drug Nomenclature Committee. Nomenclature policies and recommendations: I. Review and current proposals and decisions. Pharmacopeial Forum . 1991; 17:1509-11.

317. Desoxyn^® (methamphetamine hydrochloride) tablets—Gradumet^® tablets prescribing information. In: Barnhart ER, publisher. Physicians' desk reference. 45th ed. Oradell, NJ: Medical Economics Inc; 1991:513-4.

318. Drugs used in obesity. In: Drug evaluations subscription. Chicago, IL: American Medical Association; III/PSY-6:1-16, Winter 1992.

319. McTavish D, Heel RC. Dexfenfluramine: a review of its pharmacological properties and therapeutic potential in obesity. Drugs . 1992; 43:713-33. [PubMed 1379149]

320. Anon. Round-table discussion. Drugs . 1990; 39(Suppl 3):63-6.

321. Silverstone T. Appetite suppressants: a review. Drugs . 1992; 43:820-36. [PubMed 1379155]

322. Anon. Fluoxetine ( Prozac ) and other drugs for treatment of obesity. Med Lett Drugs Ther . 1994; 36:107-8. [PubMed 7968782]

323. Weintraub M, Sundaresan PR, Madan M et al. Long-term weight control study I (weeks 0 to 34): the enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther . 1992; 51:586-94. [PubMed 1587072]

324. Goldstein DJ, Potvin JH. Long-term weight loss: the effect of pharmacologic agents. Am J Clin Nutr . 1994; 60:647-57. [PubMed 7942569]

325. Weintraub M, Sundaresan PR, Schuster B et al. Long-term weight control study II (weeks 34 to 104): an open-label study of continuous fenfluramine plus phentermine versus targeted intermittent medication as adjuncts to behavior modification, caloric restriction, and exercise. Clin Pharmacol Ther . 1992; 51:595-601. [PubMed 1587073]

326. Weintraub M, Sundaresan PR, Schuster B et al. Long-term weight control study III (weeks 104 to 156): an open-label study of dose adjustment of fenfluramine and phentermine. Clin Pharmacol Ther . 1992; 51:602-7. [PubMed 1587074]

327. Weintraub M, Sundaresan PR, Schuster B et al. Long-term weight control study IV (weeks 156 to 190): the second double-blind phase. Clin Pharmacol Ther . 1992; 51:608-14. [PubMed 1587075]

328. Weintraub M, Sundaresan PR, Schuster B et al. Long-term weight control study V (weeks 190 to 210): follow-up of participants after cessation of medication. Clin Pharmacol Ther . 1992; 51:615-8. [PubMed 1587076]

329. Weintraub M, Sundaresan PR, Cox C. Long-term weight control study VI: individual participant response patterns. Clin Pharmacol Ther . 1992; 51:619-33. [PubMed 1587077]

330. Weintraub M, Sundaresan PR, Schhuster B. Long-term weight control study VII (weeks 0 to 210): serum lipid changes. Clin Pharmacol Ther . 1992; 51:634-41. [PubMed 1587078]

331. Weintraub M. Long-term weight control study: conclusion. Clin Pharmacol Ther . 1992; 51:642-6. [PubMed 1587079]

332. Wyeth-Ayerst Laboratories, Philadelphia, PA: Personal communication.

333. Hirsch J. Comments on "long-term weight loss: the effect of pharmacologic agents," by DJ Goldstein and JH Potvin. Am J Clin Nutr . 1994; 60:658-9.

334. Atkinson RL, Hubbard VS. Report on the NIH Workshop on Pharmacologic Treatment of Obesity. Am J Clin Nutr . 1994; 60:153-6. [PubMed 7913290]

335. NIH Technology Assessment Conference Panel. Technology assessment conference: methods for voluntary weight loss and control. Ann Intern Med . 1992; 116:942-9. [PubMed 1580453]

336. Bray GA. Barriers to the treatment of obesity. Ann Intern Med . 1991; 115:152-3. [PubMed 1760006]

337. Centers for Disease Control and Prevention Substance Abuse and Mental Health Services Administration. Increasing morbidity and mortality associated with abuse of methamphetamine—United States, 1991-1994. MMWR Morb Mortal Wkly Rep . 1995; 44:882-6. [PubMed 7476843]

338. Drug Enforcement Administration. Elimination of threshold for ephedrine. Final Rule. [21 CFR Parts 1310 and 1313] Fed Regist 1994; 59:51365-7.

339. Drug Enforcement Administration. Implementation of the Domestic Chemical Diversion Control Act of 1993 (pub. L. 103-200). [21 CFR parts 1307, 1309, 1310, 1313 and 1316] Fed Regist . 1994; 59:51887-908.

340. Drug Enforcement Administration, Washington, DC: Personal communication; 1994 Dec.

341. US Department of Justice, Washington, DC: Personal communication; 1994 Nov.

342. Anon. U-turn: states put ephedrine OTCs back behind counter. Drug Topics . 24 Oct 1994; 138:27.

343. Anon. Panels urge removal of OTC ephedrine. Generic Line . 1994; 11:5.

344. Drug Enforcement Administration. Elimination of threshold for ephedrine. Proposed Rule. [21 CFR Part 1310] Fed Regist . 1994; 59:12562-3.

345. Anon. Federal and state actions against ephedrine abuse. NC Board of Pharm . 1994; 16:2.

346. Food and Drug Administration. Cold, cough, allergy, bronchodilator, and antiasthamic drug products for over-the-counter human use; proposed amendment of monograph for OTC bronchodilator drug products. Notice of proposed rulemaking. [21 CFR Parts 310 and 341] Fed Regist 1995; 60:38643-7.

347. Removal of exemption for certain pseudoephedrine products marketed under the Food, Drug, and Cosmetic Act. Fed Regist . 1995; Oct 31. 21 CFR Parts 1309,1310,1313 [DEA-138P].

348. Public Law 104-237, 104th Cong., (3 October 1996), Comprehensive Methamphetamine Control Act of 1996 .

349. Maltz GA. Methamphetamine law will control bulk sales of “precursor chemicals”: earlier DEA ruling nullified. Pharmacy Today . 1996; 2:1,17.

350. Wyeth-Ayerst. Redux^® (dexfenfluramine hydrochloride) capsules prescribing information. Philadelphia, PA; 1996 Apr 29.

351. The United States pharmacopeia, 23rd rev, and The national formulary, 18th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1995:11-2,971-2.

352. Deitch MW. Dear health care provider letter: Pondimin^® and Redux^® to be voluntarily withdrawn. Philadelphia, PA: Wyeth-Ayerst; 1997 Sep 15.

353. Wyeth-Ayerst. Pondimin^® and Redux^® to be voluntarily withdrawn. Philadelphia, PA: 1997 Sep 15. Press release.

354. Bachorik L. FDA announces withdrawal of fenfluramine and dexfenfluramine. HHS News. P97-32. Food and Drug Administration; 1997 Sep 15.

355. Curfman GD. Diet pills redux. N Engl J Med . 1997; 337:629-30. [PubMed 9271487]

356. Lumpkin MM. FDA public health advisory: reports of valvular heart disease in patients receiving concomitant fenfluramine and phentermine. Rockville, MD: Food and Drug Administration; 1997 Jul 8.

357. Deitch MW. Dear health care provider letter regarding labeling changes for Pondimin^® and Redux^®. Philadelphia, PA: Wyeth-Ayerst; 1997 Jul 24.

358. Food and Drug Administration Center for Drug Evaluation and Research. “FEN-PHEN” update. Rockville, MD; 1997 Aug 28.

359. Food and Drug Administration. Update to FDA questions & answers on pen-phen [sic], fenfluramine or dexfenfluramine. Rockville, MD; 1997 Sep 19.

360. Connolly HM, Crary JL, McGoon MD et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med . 1997; 337:581-8. [PubMed 9271479]

361. Mark EJ, Patalas ED, Chang HT et al. Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. N Engl J Med . 1997; 337:602-5. [PubMed 9271482]

362. Wyeth-Ayerst Laboratories. Fen/phen—obesity revision: Wyeth-Ayerst to add labeling information to antiobesity therapies. Philadelphia, PA; 1997 Jul 28.

363. Anon. FDA steps up campaign to discourage off-label “fen/phen” use with public health advisory; agency coordinates message with NEJM, Mayo clinic. FDC Rep . 1997; (Jul 14):4-5.

364. Anon. Health advisory on fenfluramine/phentermine for obesity. HHS News . P97-20. Rockville, MD: Food and Drug Administration; 1997 Jul 8.

365. Anon. Knoll Meridia studies continue after Redux , Pondimin withdrawal: lawsuits call for Wyeth to fund medical monitoring of patients exposed to drugs. FDC Rep . 1997; (Sep 22):5.

366. US Food and Drug Administration. Questions and answers about Phen/fen and valvular heart disease. Rockville, MD; 1997 July 8.

367. Plutowski S (Mayo Foundation for Medical Education and Research). Valvular heart disease associated with commonly prescribed diet pills. Rochester, MN; 1997 Jul 8. Press release from Mayo website. [Web]

368. Mayo Foundation for Medical Education and Research. Information for physicians regarding pharmacologic therapy for obesity. Rochester, MN; 1997 Jul 7. Press release from Mayo website. [Web]

369. Mayo Foundation for Medical Education and Research. Heart valve disease and fen-phen: NEJM waives embargo for Mayo Clinic announcement. Rochester, MN; 1997 Jul 8. Press release from Mayo website. [Web]

370. Anon. FDA fenfluramine/ Redux epidemiological analysis of HMO records supports findings of valvulopathy in asymptomatic patients reported from five surveys. FDC Rep . 1997; (Sep 15):3-5.

371. Connolly HM, Crary JL, McGoon MD et al, for the Mayo Foundation for Medical Education and Research. Valvular heart disease associated with fenfluramine-phentermine. Rochester, MN; 1997 Jul 8.

372. Mayo Foundation for Medical Education and Research. Information and recommendations for people taking fenfluramine and phentermine. Rochester, MN; 1997 Jul 8.

373. Wyeth-Ayerst. An important message to patients who have used Pondimin^® (fenfluramine hydrochloride) tablets C-IV or Redux^® (dexfenfluramine hydrochloride) capsules C-IV. Personal communication. Sept 15, 1997.

374. Graham DJ, Green L. Further cases of valvular heart disease associated with fenfluramine-phentermine. N Engl J Med . 1997; 337:635. [PubMed 9280830]

375. Cannistra LB, Davis SM, Bauman AG. Valvular heart disease associated with dexfenfluramine. N Engl J Med . 1997; 337:636. [PubMed 9280831]

376. McCann UD, Selden LS, Rubin LJ et al. Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. JAMA . 1997; 278:666-72. [PubMed 9272900]

377. McCann U, Hatzidimitriou G, Ridenour A et al. Dexfenfluramine and serotonin neurotoxicity: further preclinical evidence that clinical caution is indicated. J Pharmacol Exp Ther . 1994; 269:792-8. [PubMed 7514223]

378. Voelker R. Obesity drug renews toxicity debate. JAMA . 1994; 272:1087-8. [PubMed 7933303]

379. Cacoub P, Dorent R, Nataf P et al. Pulmonary hypertension and dexfenfluramine. Eur J Clin Pharmacol . 1995; 48:81-3. [PubMed 7621854]

380. Davis R, Faulds D. Dexfenfluramine: an updated review of its therapeutic use in the management of obesity. Drugs . 1996; 52:696-724. [PubMed 9118819]

381. Cerda JJ. The pharmacologic management of obesity. J Fl Med Assoc . 1997; 84:89-92.

382. AH Robins. Pondimin^® (fenfluramine hydrochloride) tablets prescribing information. Richmond, VA; 1996 Nov 25.

383. Food and Drug Administration. Compounding of fenfluramine and dexfenfluramine products. Rockville, MD; 1997 Oct 2.

384. American College of Cardiology. Statement of the American College of Cardiology on recommendations for patients who have used anorectic drugs. 1997 Oct 18.

385. American College of Cardiology. ACC comments on public health recommendations for former diet drug patients. 1997 Nov 18.

386. Centers for Disease Control and Prevention. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, November 1997. MMWR Morb Mortal Wkly Rep . 1997; 46:1061-6. [PubMed 9385873]

387. Dajani AS, Taubert KA, Wilson W et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA . 1997; 277:1794-801. [PubMed 9178793]

388. Wyeth-Ayerst, Philadelphia, PA: Personal communication.

389. Ho H, Lockitch G, Eaves L et al. Blood serotonin concentrations and fenfluramine therapy in autistic children. J Pediatr . 1986; 108:465-9. [PubMed 2936877]

390. Geller E, Ritvo ER, Freeman BJ et al. Preliminary observations on the effect of fenfluramine on blood serotonin and symptoms in three autistic boys. N Engl J Med . 1982; 307:165-9. [PubMed 7088052]

391. Reviewers' comments (personal observations).

392. Medeva. Statement on obesity treatment medication and importance of physician-patient dialogue. Rochester, NY; 1997 Nov 25. Press release.

393. Medeva. Ionamin^® (C-IV) (phentermine resin capsules) prescribing information. Rochester, NY; 1997 Oct.

394. Coyne CT. Dear health care professional letter regarding labeling changes of Ionamin^® (phentermine resin capsules). Rochester, NY: Medeva; 1997 Aug 8.

395. Coyne CT. Dear doctor or health care professional letter regarding appropriate use of Ionamin^® (phentermine resin capsules). Rochester, NY: Medeva; 1997 Sep 18.

396. SoRelle R. Fen-phen and risk of valvular disease. Circulation . 1997; 96:1705-6. [PubMed 9323046]

397. Bostwick JM, Brown TM. A toxic reaction from combining fluoxetine and phentermine. J Clin Psychopharmacol . 1996; 16:189-90. [PubMed 8690835]

398. Nightingale SL. From the Food and Drug Administration: interim recommendations issued for patients exposed to fenfluramine and dexfenfluramine. JAMA . 1997; 278:1728. [PubMed 9388135]

399. Bachorik L (US Food and Drug Administration). Interim recommendations issued for patients exposed to fenfluramine and dexfenfluramine. HHS News. Press release No. P97-36. 1997 Nov 13.

400. Department of Health and Human Services. Questions and answers concerning the Department of Health and Human Services (DHHS) interim recommendations issued for patients who have taken either fenfluramine or dexfenfluramine. 1997 Nov 13.

401. Anon. Recommendations issued for patients who took fenfluramine, dexfenfluramine. Am J Health-Syst Pharm . 1998; 55:18.

402. American Heart Association National Center. Statement of the American Heart Association on recommendations for patients who have used fenfluramine/phentermine. 1997 Oct.

403. Drug Enforcement Administration. Implementation of the Comprehensive Methamphetamine Control Act of 1996; regulation of pseudoephedrine, phenylpropanolamine, and combination ephedrine drug products and reports of certain transactions to nonregulated persons. 21 CFR Parts 1300, 1309, 1310. Proposed rule. [DEA No. 163P] Fed Regist . 1997; 62:52294-304.

404. Khan MA, Herzog CA, St. Peter JV et al. The prevalence of cardiac valvular insufficiency assessed by transthoracic echocardiography in obese patients treated with appetite-suppressant drugs. N Engl J Med . 1998; 339:713-8. [PubMed 9731086]

405. Jick H, Vasilakis C, Weinrauch LA et al. A population-based study of appetite-suppressant drugs and the risk of cardiac valve regurgitation. N Engl J Med . 1998; 339:719-24. [PubMed 9731087]

406. Weissman NJ, Tighe JF Jr, Gottdiener JS et al. An assessment of heart-valve abnormalities in obese patients taking dexfenfluramine, sustained-release dexfenfluramine, or placebo. N Engl J Med . 1998; 339:725-32. [PubMed 9731088]

407. Devereux RB. Appetite suppressants and valvular heart disease. N Engl J Med . 1998; 339:765-7. [PubMed 9731094]

408. Mclean Baird I. Risks of heart-valve abnormalities with appetite suppressants. Lancet . 1998; 352:1403. [PubMed 9807983]

409. Cannistra LB, Cannistra AJ. Regression of multivalvular regurgitation after the cessation of fenfluramine and phentermine treatment. N Engl J Med . 1998; 339:771. [PubMed 9742026]

410. Anon. Another diet drug approved. Ann Intern Med . 1998; 128:336.

411. Moore TJ. Time to act on drug safety. JAMA . 1998; 279:1571-3. [PubMed 9605903]

412. Bray GA. Obesity: a time bomb to be defused. Lancet . 1998; 352:160-1. [PubMed 9683198]

413. Sjöström L, Rissanen A, Anderson T et al. Randomised placebo-controlled trial of orlistat for weight loss and prevention regain in obese patients. Lancet . 1998; 352:167-72. [PubMed 9683204]

414. National Institutes of Health, National Heart, Lung, and Blood Institute. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. Bethesda, MD, June 1998.

415. Cerulli J, Lomaestro BM, Malone M. Update on the pharmacology of obesity. Ann Pharmacother . 1998; 32:88-102. [PubMed 9475827]

416. Knoll Pharmaceutical. Meridia^® (sibutramine hydrochloride monohydrate capsules) prescribing information (dated 1998 Jan). In: Physicians' desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:1494-8.

417. Wyeth-Ayerst. Dear health care professional letter regarding valvular irregularities and primary pulmonary hypertension associated with the use of Plegine^®. Philadelphia, PA: Wyeth-Ayerst; 1998 Jun 15.

418. Dillon KA, Putnam KG, Avorn JL. Death from irreversible pulmonary hypertension associated with short-term use of fenfluramine and phentermine. JAMA . 1997; 278:1320. [PubMed 9343461]

419. Wyeth-Ayerst. Plegine^® (phendimetrazine tartrate tablets) prescribing information. In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998(Suppl A):A304.

420. SmithKline Beecham. Fastin^® (phentermine hydrochloride capsules) prescribing information. In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998(Suppl A):A292-3.

421. Medeva Pharmaceuticals. Ionamin^® (phentermine resin) prescribing information. In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998(Suppl A):A203-4.

422. National Institutes of Health Office of Medical Applications of Research. NIH Consensus statement: diagnosis and treatment of attention deficit hyperactivity disorder. 1998; 16(Nov 16-18): in press. From NIH web site [1998 Nov 19]. [Web]

423. Swanson JM, Sergeant JA, Taylor E et al. Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet . 1998; 351:429-33. [PubMed 9482319]

424. Goldman LS, Genel M, Bexman RJ et al for the Council on Scientific Affairs et al. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA . 1998; 279:1100-7. [PubMed 9546570]

425. American Academy of Child and Adolescent Psychiatry. Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry . 1997; 36(Suppl):85-121S. [PubMed 9000785]

426. Shaffer D. Attention deficit hyperactivity disorder in adults. Am J Psychiatry . 1994; 151:633-8. [PubMed 7909410]

427. Spencer T, Biederman J, Wilens TE et al. Adults with attention-deficit/hyperactivity disorder: a controversial diagnosis. J Clin Psychiatry . 1998; 59(Suupl 7):59-68. [PubMed 9680054]

428. Popper CW. Antidepressants in the treatment of attention-deficit/hyperactivity disorder. J Clin Psychiatry . 1997; 58(Suppl 14):14-29. [PubMed 9418743]

429. Smith BH, Pelham WE, Gnagy E et al. Equivalent effects of stimulant treatment for attention-deficit hyperactivity disorder during childhood and adolescence. J Am Acad Child Adolesc Psychiatry . 1998; 37:314-21. [PubMed 9519637]

430. Roche Laboratories Inc. Xenical^® (orlistat) capsules prescribing information. Nutley, NJ; 1999 Apr.

431. McNeely W, Benfield P. Orlistat. Drugs . 1998; 56:241-9. [PubMed 9711448]

432. Hollander PA, Elbein SC, Hirsch IB et al. Role of orlistat in the treatment of obese patients with type 2 diabetes: a 1-year randomized double-blind study. Diabetes Care . 1998; 21:1288-94. [PubMed 9702435]

433. Roche Laboratories Inc. Xenical^® (orlistat) capsules patient information. Nutley, NJ; 1999 Apr.

434. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry . 1999; 56:1073-86. [PubMed 10591283]

435. Taylor E. Development of clinical services for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry . 1999; 56:10979.

436. The MTA Cooperative Group. Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder. Arch Intern Med . 1999; 56:1088-96.

437. Pliszka SR, Greenhill LL, Crismon ML et al. The Texas Children's Medication Algorithm Project: Report of the Texas Consensus Conference Panel on Medication Treatment of Childhood Attention-Deficit/Hyperactivity Disorder. Part I. J Am Acad Child Adolesc Psychiatry . 2000; 39:908-19. [PubMed 10892234]

438. American Academy of Pediatrics Committee on Quality Improvement and Subcommittee on Attention-Deficit/Hyperactivity Disorder. Clinical treatment guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics . 2001; 108:1033-44. [PubMed 11581465]

439. National Institutes of Health Office of Medical Applications of Research. NIH Consensus statement: diagnosis and treatment of attention deficit hyperactivity disorder. 1998; 16(Nov 16-18): in press. From NIH web site [1998 Nov 19]. [Web]

440. American Academy of Child and Adolescent Psychiatry. Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry . 1997; 36(Suppl):85-121S. [PubMed 9000785]

441. Popper CW. Antidepressants in the treatment of attention-deficit/hyperactivity disorder. J Clin Psychiatry . 1997; 58(Suppl 14):14-29. [PubMed 9418743]

442. Goldman LS, Genel M, Bexman RJ et al for the Council on Scientific Affairs et al. Diagnosis and treatment of attention-deficit/hyperactivity disorder in children and adolescents. JAMA . 1998; 279:1100-7. [PubMed 9546570]

443. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry . 1999; 56:1073-86. [PubMed 10591283]

444. Taylor E. Development of clinical services for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry . 1999; 56:10979.

445. Shire US Inc. Adderall^® (amphetamine product) prescribing information (dated 2006 Jun). In: Physicians' desk reference online. Accessed 2006 Dec 6. [Web]

446. Shire US Inc. Adderall XR^® (mixed salts of a single-entity amphetamine product) prescribing information. Wayne, PA; 2007 Mar.

447. American Academy of Child and Adolescent Psychiatry. Practice parameter for the use of stimulant medications in the treatment of children, adolescents and adults. J Am Acad Child Adolesc Psychiatry . 2002; 41(2 Suppl):26S-49S. [PubMed 11833633]

448. Littner M, Johnson SF, McCall WV et al for the American Academy of Sleep Medicine Standards of Practice Committee. Practice parameters for the treatment of narcolepsy: an update for 2000. Sleep . 2001; 24:451-66. [PubMed 11403530]

449. US Food and Drug Administration. Adderall and Adderall XR (amphetamine): sudden death in children. Rockville, MD; 2005 Feb 9. Alert for Healthcare Professionals. From FDA website. Accessed 2009 Oct 8. [Web]

450. US Food and Drug Administration. Public health advisory for Adderall and Adderall XR. Rockville, MD; 2005 Feb. From FDA website. [Web]

451. Health Canada. Health Canada suspends market authorization of Adderall XR^®, a drug prescribed for attention deficit hyperactivity disorder (ADHD) in children. 2005 Feb 9. From Health Canada website. [Web]

452. Food and Drug Administration. Cylert and generic pemoline products [October 24, 2005]. Medwatch alert. Rockville, MD; October 2005. From FDA website. [Web]

453. Food and Drug Administration. Pemoline tablets and chewable tablets (marketed as Cylert). Alert for healthcare professionals. Rockville, MD; October 2005. From FDA website. [Web]

454. Health Canada. Health Canada allows Adderall XR^® back on the Canadian market. 2005 Aug 24. From Health Canada website. [Web]

455. Shire Pharmaceuticals. Shire announces reinstatement of Adderall XR^® in Canada. Basingstoke, UK and Philadelphia, PA; 2005 Aug 24. Press release.

456. Levine M, Gow R, Shea S. Report of the Adderall XR new drug committee. 2005 Aug 26. From Health Canada website. Accessed 2005 Oct 18. [Web]

457. Drug Enforcement Administration, Diversion Control Program. Methamphetamine Anti-proliferation Act of 2000 (MAPA), thresholds of pseudoephedrine & phenylpropanolamine drug products resulting from the Methamphetamine Anti-proliferation Act of 2000 (MAPA). From Department of Justice Drug Enforcement Administration, Diversion Control Program website. [Web]

458. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. The Children's Health Act of 2000: a summary, title XXXVI Methamphetamine Anti-proliferation. From SAMHSA website. [Web]

459. GlaxoSmithKline. Dexedrine^® (dextroamphetamine sulfate) Spansule^® sustained-release capsules and tablets prescribing information. Research Triangle Park, NC; 2007 Mar.

460. United States. Senate and House of Representatives. 109th Congress. H.R. 3199. An act to extend and modify authorities needed to combat terrorism, and for other purposes (the USA Patriot Act Improvement and Reauthorization Act of 2005). From the Library of Congress website. Accessed May 16, 2006. [Web]

461. Horrigan JP. Dear healthcare professional letter: Important prescribing information about Dexedrine^®. Research Triangle Park, NC: GlaxoSmithKline; 2006 Aug 4.

462. Young D. Cardiovascular, psychiatric warnings strengthened on Adderall: FDA seeks stronger warnings on all ADHD drugs. ASHP News. Bethesda, MD: American Society of Health-System Pharmacists; 2006 Jul 28. From ASHP website. [Web]

463. Shire US Inc. Vyvanse^® (lisdexamfetamine dimesylate) capsules prescribing information. Wayne, PA; 2007 Feb.

464. Anon. Lisdexamfetamine dimesylate (Vyvanse) for ADHD. Med Lett Drugs Ther. 2007; 49:58-9.

465. Amphetamine. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2015:65-8.

466. US Food and Drug Administration. FDA directs ADHD drug manufacturers to notify patients about cardiovascular adverse events and psychiatric adverse events. FDA News February 21, 2007. From FDA web site. [Web]

467. GlaxoSmithKline. Dexedrine^® (dextroamphetamine sulfate) Spansule^® sustained-release capsules and tablets medication guide. Research Triangle Park, NC; 2007 Mar.

468. Shire US Inc. Adderall XR^® (mixed salts of a single-entity amphetamine product) medication guide. Wayne, PA; 2007 Mar.

469. US Food and Drug Administration. AHRQ and FDA to collaborate in largest study ever of possible heart risks with ADHD medications. FDA News September 17, 2007. From FDA web site. [Web]

470. American Gastroenterological Association. American Gastroenterological Association medical position statement on obesity. Gastroenterology . 2002; 123:879-81. [PubMed 12198714]

471. Klein S, Wadden T, Sugerman HJ. AGA technical review on obesity. Gastroenterology . 2002; 123:882-932. [PubMed 12198715]

472. Snow V, Barry P, Fitterman N et al. Pharmacologic and surgical management of obesity in primary care: a clinical practice guideline from the American College of Physicians. Ann Intern Med . 2005; 142:525-31. [PubMed 15809464]

473. Vetter VL, Elia J, Erickson C et al. Cardiovascular monitoring of children and adolescents with heart disease receiving stimulant drugs: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation . 2008; 117:2407-23. [PubMed 18427125]

474. Perrin JM, Friedman RA, Knilans TK et al. Cardiovascular monitoring and stimulant drugs for attention-deficit/hyperactivity disorder. Pediatrics . 2008; 122:451-3. [PubMed 18676566]

475. Food and Drug Administration. FDA Alert: Information for healthcare professionals: Communication about an ongoing safety review of stimulant medications [dexmethylphenidate (marketed as Focalin, Focalin XR), dextroamphetamine (marketed as Dexedrine, Dexedrine Spansules, Dextrostat, and generics), lisdexamfetamine (marketed as Vyvanse), methamphetamine (marketed as Desoxyn), methylphenidate (marketed as Concerta, Daytrana, Metadate CD, Metadate ER, Methylin, Methylin ER, Ritalin, Ritalin-LA, and Ritalin-SR), mixed salts amphetamine (marketed as Adderall and Adderall XR), and pemoline (marketed as Cylert and generics)] used in children with attention-deficit/hyperactivity disorder (ADHD). Rockville, MD; 2009 Jun 23. From the FDA website. [Web]

476. Gould MS, Walsh BT, Munfakh JL et al. Sudden death and use of stimulant medications in youths. Am J Psychiatry . 2009; 166:992-1001. [PubMed 19528194]

477. Vitiello B, Towbin K. Stimulant treatment of ADHD and risk of sudden death in children. Am J Psychiatry . 2009; 166:955-7. [PubMed 19528196]

478. Food and Drug Administration. FDA Drug Safety Communication: Safety review update of medications used to treat attention-deficit/hyperactivity disorder (ADHD) in children and young adults. 2011 Nov 1. From FDA website. Accessed 2015 Jul 24. [Web]

479. Food and Drug Administration. FDA Drug Safety Communication: Safety review update of medications used to treat attention-deficit/hyperactivity disorder (ADHD) in adults. 2011 Dec 12. From FDA website. Accessed 2015 Jul 24. [Web]

480. Habel LA, Cooper WO, Sox CM et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA . 2011; 306:2673-83. [PubMed 22161946]

481. Cooper WO, Habel LA, Sox CM et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med . 2011; 365:1896-904. [PubMed 22043968]

482. Teva Pharmaceuticals USA, Inc. Adderall^® (mixed salts of a single-entity amphetamine product) prescribing information. North Wales, PA; 2016 Sep. [Web]

483. Shire US Inc. Adderall XR^® (mixed salts of a single-entity amphetamine product) prescribing information. Lexington, MA; 2017 Jan.

484. Shire US Inc. Vyvanse^® (lisdexamfetamine dimesylate) capsules and chewable tablets prescribing information. Lexington, MA; 2017 Jul.

485. Hood B, Nowicki MJ. Eosinophilic hepatitis in an adolescent during lisdexamfetamine dimesylate treatment for ADHD. Pediatrics . 2010; 125:e1510-3. [PubMed 20457690]

486. Arbor Pharmaceuticals. Evekeo^® (amphetamine sulfate) tablets prescribing information. Atlanta, GA; 2016 Sep.

487. American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation . 2006; 114:e84-231. [PubMed 16880336]

500. FDA drug safety communication. FDA updating warnings to improve safe use of prescription stimulants used to treat ADHD and other conditions; issued May 11 2023. From FDA website. [Web]