Amphetamine, methamphetamine, methylphenidate, and other psychostimulants have a number of adverse effects, including death. While in most cases fatalities result from overdoses of psychostimulants, death very rarely occurs in certain individuals using therapeutic or low doses. This chapter describes amphetamine intoxication, adverse effects associated with acute and chronic amphetamine use, amphetamine-related psychiatric disorders, and mortality associated with amphetamine use, including rare instances of sudden deaths in children prescribed ADHD medications.
The U.K. pharmacologist Leslie Iversen reports that millions of people have used moderate doses of amphetamine, usually taken orally, for many years without any overt signs of physical or mental harm. However, individuals who become dependent on amphetamine or methamphetamine, especially those who self-inject, insufflate (snort), or smoke the drugs, are likely to suffer a variety of serious adverse effects (Iversen 2008, 147).
Amphetamines and related sympathomimetic amines exert most of their intended effects by stimulating effector organs that are innervated by adrenergic nerves. Expected effects of psychostimulants, which may be adverse, include elevated blood pressure, constriction of peripheral vessels, stimulation of heart muscles, relaxation of bronchial and intestinal muscles, dilation of pupils, and stimulation of the cerebrospinal axis, especially the brain stem and cortex. In addition, amphetamine is a potent agent for stimulating the medullary respiratory center, lessening the degree of central depression caused by anesthetic, narcotic, and hypnotic drugs.
Neuronal release of dopamine (courtesy Marvin G. Miller).
Animals given large amounts of amphetamine exhibit tremors, restlessness, increased motor activity, agitation, and sleeplessness to a degree not observed after the weaker stimulant ephedrine (Goodman and Gilman 1955, 518). Both acute and chronic instances of excess drug use in humans cause similar effects and various other manifestations of amphetamine toxicity. People who abuse amphetamines and are dependent on them are often very thin with puffy skin, skin sores, dilated pupils, reddened eyes and dental problems. They may also have a tremor and appear nervous, and they often talk and move quickly. People dependent on amphetamine tend to be preoccupied with making sure they don’t run out of their prescription or drug source. Then again, some people who abuse amphetamines take care to keep symptoms under control but remain preoccupied with having a steady drug supply and the money to pay for it.
The psychic effects of amphetamine have been studied in great detail and vary depending on the mental state and personality of the individual and the dose administered. After a dose of 10–30 mg amphetamine, most individuals experience wakefulness, alertness, increased initiative, elevation of mood, enhanced confidence, euphoria, elation, lessened sense of fatigue, increased motor and speech activity and increased ability to concentrate (Goodman and Gilman 1955, 518). The effect on psychomotor performance, as described in Chapter Five, is characterized by increased workload productivity, although the number of errors isn’t necessarily decreased. The initiative rather than the ability to perform mental work is increased.
The effects of amphetamine aren’t always pleasurable. In some people, low doses of amphetamine cause tremor, palpitations and edginess. Even people who previously experienced pleasurable effects from amphetamine and methamphetamine may find these effects reversed, especially by overdosage or repeated use of medication. Adverse psychic effects include headache, palpitations, dizziness, vasomotor disturbances, agitation, confusion, dysphoria, apprehension, delirium, depression, and fatigue. Large doses are nearly always followed by fatigue and mental depression (Goodman and Gilman 1955, 518–9).
Psychostimulant drugs can cause a number of adverse effects that vary depending on the type of stimulant being used and the individual’s unique biology (e.g., drug metabolizing genes, general health, other medications). Information listed in the 2002 Physicians’ Desk Reference for the following psychostimulants, which are approved for the treatment of ADHD, is based on the results of clinical trials and post-marketing observations.
As a treatment for ADHD, the following drugs are recommended as part of a comprehensive treatment program including psychological, educational and social measures. The National Library of Medicine’s drug information division states that appropriate educational placement is essential and psychosocial intervention is often helpful as part of a comprehensive treatment approach for ADHD (National Library of Medicine Daily Med 2007).
The entries for these drugs open with a boxed warning:
Amphetamines have a high potential for abuse. Administration of amphetamines for prolonged periods of time may lead to drug dependence and must be avoided. Particular attention should be paid to the possibility of subjects obtaining amphetamines for non-therapeutic use or distribution to others, and the drugs should be prescribed or dispensed sparingly [Physicians’ Desk Reference 2002].
• Cardiovascular effects include palpitations, tachycardia, and elevation of blood pressure. There have been isolated reports of cardiomyopathy (heart muscle damage) with chronic amphetamine use.
• Central nervous system effects include psychotic episodes that can rarely occur at recommended doses, overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, tremor, headache, exacerbation of motor and phonic tics and Tourette’s syndrome.
• Gastrointesinal effects include mouth dryness, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances, anorexia, and weight loss.
• Allergic effects include urticaria (itching).
• Endocrine effects include impotence and changes in libido.
Drug abuse and dependence: amphetamines have been extensively abused. Tolerance, extreme psychological dependence and severe social disability have occurred. There are reports of patients who have increased the dosage to many times that recommended. Abrupt cessation following prolonged high dose administration results in extreme fatigue and mental depression; changes are also noted on the sleep electroencephalogram. Amphetamines have also been reported to exacerbate motor and phonic tics and Tourette’s syndrome.
Methylphenidate is a mild central nervous system stimulant. Its mode of action in man is not completely understood, but it presumably activates the brain stem arousal system and cortex to produce its stimulant effects. Compared to dextroamphetamine, an equivalent dose of methylphenidate is about three times greater (i.e., 10 mg dextroamphetamine is comparable to 30 mg methylphenidate). Worldwide, methylphenidate is the most commonly used stimulant in conditions of ADHD.
The entry for methamphetamine opens with a boxed warning:
Methamphetamine has a high potential for abuse. Administration of methamphetamine for prolonged periods of time may lead to drug dependence and must be avoided. Particular attention should be paid to the possibility of subjects obtaining methamphetamine for non-therapeutic use or distribution to others, and the drug should be prescribed or dispensed sparingly [Physicians’ Desk Reference 2002].
• Cardiovascular effects include palpitations, tachycardia, and elevation of blood pressure.
• Central nervous system effects include psychotic episodes that can rarely occur at recommended doses, overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, tremor, headache, exacerbation of motor and phonic tics and Tourette’s syndrome.
• Gastrointesinal effects include mouth dryness, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances, anorexia, and weight loss.
• Allergic effects include urticaria (itching).
• Endocrine effects include impotence and changes in libido. Amphetamines can cause a significant elevation in plasma corticosteroid levels, with the greatest increases seen in the evening. Amphetamines may interfere with urinary steroid determinations.
• Miscellaneous effects include rhabdomyolysis associated with high doses and suppression of growth in children. Insulin requirements in diabetes mellitus may be altered in association with the use of methamphetamine and weight loss.
According to the Centers for Disease Control and Prevention, in 2007 in the United States, 2.05 million children between the ages of 5 to 11 were reported to have ADHD (7.4 percent), and 2.4 million children between the ages of 12 to 17 were reported to have ADHD (9.7 percent) with Colorado having the lowest incidence and Alabama having the highest. Between 1997 and 2006 the incidence of ADHD in the U.S. increased by 3 percent (http://www.help4adhd.org/en/about/statistics accessed Jan. 10, 2010). Consequently, there are increasing number of children on psychostimulant medications and more reports of serious adverse events.
Serious cardiovascular events, including sudden deaths, have occurred in children and adults on ADHD medications.
Researchers at Columbia University/New York State Psychiatric Institute in New York City conducted a study at the request of the FDA in which they evaluated mortality data from 1985 through 1996. Subjects included 564 children from ages 7 to 19 years who were prescribed amphetamine, dextroamphetamine, methamphetamine, or methylphenidate according to informant reports or as noted in medical examiner records, toxicology results, or death certificates. The children were age-matched with 564 control subjects who had been killed in auto accidents.
After ruling out other causes of death such as sickle cell anemia or cerebral palsy in the ADHD treated group, the researchers found 10 youths with no other obvious causes of death. This data showed that the odds of sudden death were 7.4 times higher for children taking stimulant medications. The researchers advised that children who had been on stimulants for some time did not have a cause for concern. However, before prescribing ADHD medications for new patients, they should be evaluated for cardiac abnormalities or for a family history of sudden death (Gould et al., 2009).
Sudden deaths, stroke, and myocardial infarction have been reported in adults taking stimulant drugs at usual doses for ADHD. Although the role of stimulants in these adult cases is unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Adults with cardiac abnormalities should generally not be treated with stimulant drugs (National Library of Medicine Daily Med 2007).
Researchers at the University of Texas Southwestern Medical Center examined data from more than 3 million people between 18 and 44 years and found a link between amphetamine abuse and heart attacks. Amphetamines may contribute to heart attacks by increasing heart rate and blood pressure and by causing inflammation and artery spasms that limit blood to the heart muscle (UT Southwestern Medical Center 2008).
The use of stimulants may worsen symptoms of behavior disturbance and thought disorder in patients with pre-existing psychotic disorders.
Studies in children 7 to 10 years old using methylphenidate or a placebo over 14 months and in children 10–13 years old over a period of 36 months suggest that consistently medicated children (7 days, year-round) have a temporary slowing in growth rate, averaging a total of 2 cm less growth in height and 2.7 kg less growth in weight over 3 years (National Library of Medicine Daily Med 2007).
Difficulties with accommodation and blurring of vision have been reported in individuals using stimulant medications.
Amphetamines and other stimulants used to treat ADHD can increase the risk of seizures in some individuals with seizure disorders.
Toxic effects of amphetamine are usually extensions of the therapeutic actions of the drug and usually, but not always, occur as a result of overdosage. Although toxicity usually occurs with high doses of psychostimulants, toxicity has occurred at doses as low as 2 mg dextroamphetamine. There is no single antagonist drug that can be used in an emergency to block all adverse effects related to an amphetamine overdose. Symptomatic therapies are used. For instance, beta blockers and other antihypertensive drugs are used to counteract hypertension and overstimulation of the heart. The anti-psychotic drug haloperidol (Haldol) is used the help block the psychostimulant effects which can lead to violent behavior.
Amphetamine and also methylphenidate intoxication can occur as a physical or mental syndrome. The physical symptoms of amphetamine intoxication are the result of overstimulation of the sympathetic and central nervous systems. Therefore, toxicity can occur at lower drug doses when they’re used in combination with other stimulants, including certain cold and allergy medications, such as pseudoephedrine. Symptoms typically occur between one and two hours after ingestion of the drug and increase in intensity over the course of the next 24 to 48 hours depending on the dose of the drug and treatment (Kalant 1966, 22).
The most prominent symptoms are due to cerebral actions of amphetamine and include dizziness, increased reflexes, restlessness, anxiety, tremor, insomnia, talkativeness, tenseness, and irritability. Other symptoms seen in amphetamine intoxication include confusion, aggression, increased libido, hallucinations, delirium, panic states, and suicidal or homicidal tendencies (Goodman and Gilman, 1955). High doses of psychostimulants may also result in a dangerously high body temperature and an irregular heartbeat. One of the most serious cerebral effects is amphetamine psychosis (also see Chapter Two), which may be difficult to distinguish from schizophrenia. When amphetamine intoxication gives rise to a primarily mental syndrome, it’s characterized by vivid auditory and visual hallucinations and by delusions of persecution usually without disorientation or confusion. In a series of 54 cases of amphetamine intoxication described by Kalant, 30 of the cases involved a mental syndrome (Kalant 1966, 23).
Untoward effects on the gastrointestinal tract include dry mouth, metallic taste, anorexia, nausea, vomiting, and diarrhea. Cardiovascular effects include chilliness, pallor or flushing, sweating, palpitation, marked hypertension or hypotension, headache, diuresis, extrasystoles and other arrhythmias, anginal pain, circulatory collapse, and syncope. Convulsions and coma are usually terminal events. Hemorrhages, especially in the brain, are the main pathological findings in humans and animals dying from acute amphetamine poisoning.
At least 299 different drugs are reported to interact with amphetamine and amphetamine-like drugs. This includes more than 1855 different brand name and generic drugs (http://www.drugs.com/drug-interactions/amphetamine-dextroamphetamine,adderall.html accessed May 1, 2010). Some amphetamines and amphetamine-like compounds may also cause serotonin release and can interact with Prozac and other selective serotonin reuptake inhibitor (SSRI) drugs even weeks after drug use. (http://www.drugs.com/drug-interactions/adderall-with-prozac-190–1645–1115–648.html accessed May 1, 2010). Excess serotonin production caused by a combination of drugs can lead to a potentially fatal condition known as serotonin syndrome. As a general rule, amphetamines and other sympathomimetic amines should not be combined with SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs). Close monitoring for enhanced psychostimulant effects and possible serotonin syndrome is recommended if these agents must be used together.
Symptoms of the serotonin syndrome may include mental status changes, including irritability, altered consciousness, memory impairment, confusion, hallucinations, and coma; autonomic dysfunction changes including tachycardia, hyperthermia, diaphoresis, shivering, blood pressure fluctuations, and dry eyes; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.
From 1939 to 1952, there were at least fifty-four reported cases of acute amphetamine poisoning in America and the U.K. and many more cases in Japan and Sweden. In 1958 alone thirty-eight cases of acute amphetamine poisoning in children younger than five years of age had been reported to the Boston Poison Information Center (Grinspoon and Hedblom 1975, 138). A list of signs and symptoms of amphetamine poisoning first compiled by P.H. Connell in the 1950s includes flushing, pallor, tachycardia, serious cardiac problems, gastrointestinal disturbances, tremor, ataxia, anorexia, dryness of the mouth, insomnia, headache, dizziness, vasomotor disturbances, excessive sweating, muscular pain, rapid or slurred speech, irritability, dilation of pupils, fever, and profound collapse (Grinspoon and Hedblom 1975).
The first reports of amphetamine psychosis (described in Chapter One) in patients using amphetamines emerged in 1938. Psychiatrists enamored with amphetamines explained that the patients must have had underlying psychotic tendencies that were unmasked by the drugs.
In 1958, U.K. psychiatrist Philip Connell confronted the medical community with the inconvenient truth in the form of a detailed study. In his study of amphetamine psychosis, Connell investigated 40 institutionalized patients diagnosed with psychosis related to amphetamine use. Although some of these patients used amphetamine recreationally, more than one-third of them had originally been prescribed amphetamine tablets by a doctor. This demonstrated to Dr. Connell that psychosis could occur in anyone using the drug and not just thrill-seekers using high doses. The psychosis generally took time to develop as patients continued to take higher doses of the drug. Connell also found that the amount of amphetamine needed to induce psychosis varied (Rasmussen 2008a, 140).
Critics such as Philadelphia physician Henry Grahn, who helped Smith, Kline and French launch Dexamyl, disagreed with Connell’s findings. In an article published later in 1958, Grahn expressed his views that, considering how many people were using amphetamines, the few reports of psychosis were negligible. He did report encountering a few patients who had become habituated to the drug. Regarding these cases, Grahn wrote that these patients were healthy and productive. He went on to explain that a heavy amphetamine habit was not due to any pharmacologic action of the drug. Rather, it was due to a factor in the individual’s personal make-up that leads him to abuse drugs (Grahn 1958).
Medical science, however, couldn’t disregard the growing number of patients using amphetamines who were admitted to emergency rooms and mental wards in the late 1950s. Although the World Health Organization recognized amphetamine dependence as a problem, the question of psychosis seemed to be at a stalemate. Historical accounts suggest that too many patients and doctors liked the effects of amphetamines to rock the boat.
In response, pharmaceutical companies introduced new amphetamine-like compounds such as phenmetrazine, phentermine, and diethylpropion that they marketed as having the benefits of amphetamines without the problems related to drug dependence. In 1972, congressional hearings recognized that amphetamines as well as the newer diet pills caused problems of dependency as well as abuse (U.S. Congressional Hearings 1972). By that time some of the other newer psychostimulants, including methylphenidate, had been found to induce psychosis.
In the debates surrounding psychosis, several researchers reported that their patients had pre-morbid psychiatric conditions or characteristics, primarily alcoholism, that put them at risk for developing psychosis. In their intensive review, Grinspoon and Hedblom state that cases of amphetamine psychosis do exist where, in view of the patient’s premorbid personality, amphetamine can be considered only a precipitant. They go on to say that the ambulatory schizophrenic or preschizophrenic is likely to find amphetamine an attractive drug that works to combat the progressive failure in adaptation, loss of energy, and inability to cope with work that are symptoms of incipient schizophrenia. In these cases, amphetamine may either bring about psychosis or end the remission of a chronic ambulatory schizophrenic (Grinspoon and Hedblom 1975, 117).
As an example they describe a female college student who may have been susceptible to a schizophrenic break (she daydreamed to the point that it interfered with her school performance). She was prescribed Dexedrine, 5 mg, three times a day, for weight loss. Her initial observations on amphetamine were that she felt special, super, and began to really get into music, although nature (e.g., grass, water) made her depressed. After 3–4 weeks, her feelings of elation began to be accompanied by thoughts of suicide. She made one half-hearted suicide attempt using aspirin around that time. Soon she began to notice that she felt detached from what she was doing, as if she were observing her own actions. She eventually quit using Dexedrine, although she continued working with a psychiatrist. Several years later she took 150 mg diethylpropion (Tenuate), an amphetamine congener, which is twice the usual recommended dose. She soon experienced feelings of paranoia and doom. This relapse was temporary and all symptoms disappeared within 4 days after taking diethylpropion (Grinspoon and Hedblom 1975, 119–20). The researchers concluded that premorbid disorders make the development of psychosis more likely, but that they do not need to be present for psychosis to occur.
Chronic amphetamine intoxication causes symptoms and signs similar to those seen in acute amphetamine intoxication. However, with chronic use, abnormal mental phenomena are particularly prominent and weight loss may be marked. The physical condition of chronic amphetamine abusers is often very poor. Manifestations of chronic intoxication include severe dermatoses, malnutrition, repetitive chewing and teeth grinding, marked insomnia, irritability, hyperactivity, dental problems including ulcers of the tongue and mouth, and personality changes. In addition, skin ulcers and abscesses are common and may be associated with compulsive scratching or with poor hygiene in the intravenous injection of the drugs in individuals who self-inject (Iversen 2008, 146).
Because of the excessive release of norepinephrine induced by high doses of amphetamines, the cardiovascular system is often affected. In chronic amphetamine use, there are reports of cardiac myopathy, multiple extrasystoles, arrhythmias, hypertension, orthostatic hypotension and heart block, which can be fatal in overdoses. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia. This is rarely seen with the oral use of amphetamines, although it is common in individuals who smoke or inject amphetamines. Drug-induced damage to blood vessels in the brain can also lead to stroke (Iversen 2008, 146).
There have been several reports of cognitive impairment related to the chronic abuse of amphetamines. The most significant effects have been seen in heavy methamphetamine users and those rated to have a high level of drug dependency. Effects include an impaired ability to focus attention and manage distraction. Brain imaging with MRI also showed less brain activity in the drug subjects compared to controls in regions of the brain normally activated by decision-making. Cognitive impairments have been shown to persist for at least 3 months following a period of withdrawal and abstinence, although deficits in handling verbal material may persist for longer periods (Iversen 2008, 143).
The toxic dose of amphetamine is highly variable. Individuals vary in their reactions to amphetamine, and their general health also has and affect on drug susceptibility. Occasional, idiosyncratic reactions can occur that cause alarming symptoms. Toxicity is rarely seen in doses below 15 mg although alarming reactions have occurred after 30 mg doses, and toxicity has been reported in a dose as low as 2 mg. A dose of 120 mg ingested in a short period of time has been known to cause death, although people have survived doses higher than 500 mg (Goodman and Gilman 1955, 523).
The chronic use of amphetamines can easily lead to a variety of ills, including drug dependence. Dependence is often associated with a progressive severance of social relationships, family ties and friendships.
An example of the social problems caused by amphetamines is the devastating effect of the methamphetamine epidemic in Hawaii in the mid–1990s, which destroyed the social fabric of close-knit community life. “Ice,” a new and highly pure form of D-methamphetamine, emerged in Hawaii in the 1980s. Imported from the Far East where it was first developed, ice (called batu in Hawaii) was commonly smoked or injected. Because of government measures to eliminate cannabis in Hawaii, many Hawaiians (often unaware that ice was methamphetamine) began using the highly addictive ice. Before long, many people were dependent on ice and found their lives revolving around ways to get more of the drug.
Amphetamines used to excess can cause patients to follow repetitive behaviors and isolate themselves from anyone but other users. This social phobia caused intravenous-using methamphetamine addicts to live together in the Haight-Ashbury district of San Francisco in the late 1960s, an area where methamphetamine was readily available. At the time, motorcycle gangs headquartered in California manufactured and distributed most of the illicit methamphetamine in the United States. With 1970s restrictions on the pharmaceutical manufacture of amphetamines, demand for homemade speed grew. This strengthened the position of the motorcycle gangs and kept methamphetamines on the fringes of mainstream society.
With any drug dependence, there are financial concerns. Finding the money to pay for amphetamines can lead to theft and other crimes, including drug dealing. In addition, the chronic use of amphetamines associated with drug dependence can lead to poor work performance, which can interfere with chances for gainful employment. Violence and crime often accompany chronic amphetamine use. Some of the earliest reports came from Japan during the post-war methamphetamine epidemic. Of the 60 murderers convicted in May and June 1954 in Japan, more than half were methamphetamine users. During the same time frame, more than 10,000 people were arrested under the Awakening Drug Control Law, and more than half of these were abusers of methamphetamine.
Methamphetamine abuse can cause paranoid thinking, emotional lability, panic, and lowered impulse control, all factors that can contribute to violence. Grinspoon and Hedblom report that the amphetamines have psychopharmacological properties that potentiate or disinhibit aggressive impulses and promote paranoid thinking and delusions, providing them a greater potential for producing violence than opiates. Grinspoon and Hedblom describe three properties of amphetamine abuse that can be regarded as mutually reinforcing risk factors for violent and criminal behavior.
1. High doses of amphetamines cause the individual to focus on immediate close-range stimuli. This can lead to the impulsive lashing out at innocent bystanders.
2. Amphetamines can enhance the user’s immediate awareness of stimuli, sensory cues, and visible objects or persons. This flood of sensory information is often accompanied by psychotic paranoia.
3. Amphetamine intoxication causes psychomotor effects that energize the individual, prompting him to do something, including repetitious meaningless tasks (punding). If others try to interfere or disapprove of this behavior, the amphetamine abuser may respond with violent rage. Such violent retaliation helps to relieve the user’s pent-up feelings of psychic and muscular tension. For some, beatings, stabbings, shootings, and sometimes sadistic torture become a way of life (Grinspoon and Hedblom 1975, 189–91).
Self-injurious behaviors are also sometimes seen in amphetamine users. These behaviors include self-biting, head-banging, scratching, cutting, hair-pulling, and other forms of tissue damage. Chronic amphetamine or methamphetamine users may develop sores and skin abscesses on their bodies from repeated scratching at imaginary “crank bugs” (Iversen 2008, 143).
Untoward reactions to drugs purchased online or from illegal sources are also common. Illicit drugs may contain chemical contaminants or other substances that can be injurious to health. In 2009, a number of fatalities were reported worldwide, including in the United States, by sexual enhancers purchased online that contained hypoglycemic agents (http://www.emaxhealth.com/1035/48/29392/low-blood-sugar-fatalities-linked-illegal-sexual-enhancers.html accessed March 1, 2010).
Intravenous use of amphetamines can lead to bacterial infections at the site of injection and can cause systemic infections (septicemia), which can be lethal. Poor hygiene and sharing needles increase the risk of viral infections, including HIV, hepatitis B, and hepatitis C. Methamphetamine has also been shown to suppress the immune system, interfering with its ability to respond to infectious agents and increasing the risk of serious infection. Methamphetamine abuse is common among homosexual men who use the drug to increase sexual energy and stamina. In major cities of the U.S. the incidence of HIV infection, syphilis, and chlamydia are again on the rise, and methamphetamine is suspected of contributing to this increase (Iversen 2008, 147).
The toxic effects of amphetamines result from the release of catecholamines, especially dopamine and norepinephrine, from the presynaptic terminals of dopamine-producing neurons. Common features seen in toxicity are similar to those seen in cocaine overdoses and include tachycardia, dysrhythmias, hypertension, hyperthermia, agitation, delirium, seizures, hyperreflexia, diaphoresis, tachypnea, and rhabdomyolysis. By 1963 there were ten accounts of death by amphetamine poisoning in the medical literature. In describing the 10th amphetamine death, the researchers Zalis and Parmley report that the suggested lethal dose of amphetamine of 20 mg/kg was too high, as all fatalities to date had used smaller doses. They suggested that a lethal dose as low as 5 mg/kg was more reasonable for individuals who are particularly sensitive to amphetamine (Grinspoon and Hedblom 1975, 138).
By 1970, 43 deaths due to amphetamine overdoses or from complications related to its administration were reported worldwide, and from 1991 to 1994 medical-examiner confirmed deaths related to methamphetamine alone rose from 151 to 433 (Wallace and Squires 2000). Amphetamines have also been associated with fatalities caused by motor vehicle accidents and suicides. Morbidity and mortality reports from the CDC indicate that amphetamine tests conducted in 13 states on 38 percent of the 7,277 individuals who had committed suicide in these states in 2004 showed that 3.9 percent of the victims died with amphetamine in their system (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5546a1.htm accessed March 1, 2010).
In one case report from 2000, doctors in Greeley, Colorado, described a massive ingestion of methamphetamine associated with hyperpyrexia (increased body temperature). A 19-year-old man was arrested after a traffic violation and taken to jail. There, he told his cellmates that he had ingested 8 balls containing 8 grams of methamphetamine. An hour and a half after his arrest, the emergency medical service was called to treat the man for possible withdrawal symptoms. Upon arrival at the emergency room, the patient could speak with difficulty, and the response team saw no indication of seizures, although they witnessed severe rigors with diaphoresis. Vital signs showed a rectal temperature greater than 108°F, pulse was 180 beats per minute and blood pressure was 186/96.
Ice packs were applied to the groin, underarms and neck, which lowered his temperature to 105.5°F. The patient displayed diffuse rigidity and tremulousness; his eyes were dilated, and he did not respond to painful or verbal stimuli. Gastric lavage showed a string, but there were no pill fragments. The patient was intubated, given antihypertensive drug treatment and moved to the critical care unit. His blood amphetamine level was tested and results were extremely high (3.5 mg/L). The patient remained comatose and within two days lab tests showed abnormal blood clotting results, evidence of muscle breakdown, and elevated liver enzymes. Despite aggressive measures the patient succumbed to amphetamine toxicity 16 days after his overdose. This represents the longest survival in a patient with such a dramatic peripheral blood amphetamine level (Wallace and Squires 2000).
By 1966, accidental overdoses in small children (between 1 and 7.5 years) who had access to bottles containing amphetamine pills had rarely occurred. Prior to 1966, 19 reports of acute amphetamine poisoning in small children were made worldwide, 10 of which occurred in the United States. The doses causing toxicity and lethality have been considerably variable. Reported incidents include a dose of 10 mg causing toxicity in a 27-month-old; a 40 mg dose causing death in a 3-year-old boy; and 115 mg causing toxicity in a 32-month-old boy who recovered after 5 days (Kalant 1966, 22).