Amphetamines are stimulant drugs with biochemical effects very similar to those of the natural hormone adrenaline. Stimulants such as amphetamine have a wide range of physiological effects that make them effective medical therapies. Some of these effects, particularly amphetamine’s ability to make its users feel more awake and somewhat euphoric, also cause a potential for abuse. While most people who use amphetamines for medical purposes do not abuse them, a few historic incidents and epidemics of amphetamine abuse have led to a number of different government restrictions that may interfere with their availability as effective medical therapies. This chapter is an introduction to amphetamines and related psychostimulant drugs, including their chemical properties, history and their physiological effects.
Amphetamines are synthetic drugs developed in chemical laboratories more than 100 years ago. However, plants with amphetamine-like properties such as Ephedra have been in use for more than 5000 years. Despite this long history, since the first Benzedrine inhaler emerged in 1932, each new generation has made their own claim to drugs of this class.
Overall, the legitimate uses and occasional abuses of amphetamine compounds haven’t changed much over the years. As early as 1935, low doses of amphetamines were found to usually induce alertness, focus attention, improve confidence, increase blood pressure, induce weight loss, effectively treat narcolepsy, and relieve depression. Numerous studies showed that most subjects liked the effects of amphetamines.
Somewhat large doses of amphetamine (20–50 mg of D-amphetamine daily or more than 30 mg of mixed amphetamine salts) intensify amphetamine’s effects. As a result, at higher doses the relaxed alertness induced by low doses of amphetamine is usually replaced by a driven feeling. At higher than recommended doses, thoughts scatter through the mind quickly, increased talkativeness exhausts and bores one’s listeners, and the ability to concentrate is diminished (Iversen 2008, 14). Early studies and observations also showed that high doses of amphetamine could cause a stereotypical behavior pattern characterized by restlessness and agitation, hypertension, and, in some cases, psychosis.
Today, the effects first seen in the 1920s and 1930s with low doses of amphetamines make them an effective treatment for attention deficit hyperactivity disorder (ADHD) in children and adults, a valuable treatment for narcolepsy, an aid in weight loss, and a magnet for those desiring some degree of performance enhancement or nervous system stimulation. In conditions such as ADHD where dopamine levels are typically low, amphetamines used at low doses have a calming rather than stimulating effect, presumably because the drug helps to restore diminished dopamine levels.
High doses of amphetamine, and even more so its cousin methamphetamine, are known to lead to behavioral aberrations, toxicity, and drug abuse. Despite amphetamine’s proven medical benefits, concerns over drug abuse and neurotoxicity represent the crux of the amphetamine debate. Concern isn’t surprising given the highly publicized accounts of amphetamine misuse and abuse by a small number of individuals over the years, some of which are described later in this chapter. Still, amphetamine’s ability to improve attention and focus is causing researchers to have second thoughts. More researchers are considering the use of amphetamine and related drugs as learning aids in students and cognitive enhancers in aging adults (see Chapter Nine).
Amphetamine is a manufactured chemical closely related to several naturally occurring substances, particularly phenethylamine, an amino acid found in some cheeses and wines. The only difference in the chemical structures of amphetamine and phenethylamine is amphetamine’s inclusion of a methyl (CH3) group attached to its side chain. This prevents degradation of amphetamine by the enzyme monoamine oxidase during digestion. Consequently, amphetamine can enter the bloodstream and persist for fairly long periods.
The D and L isomers of amphetamine (courtesy Marvin G. Miller).
This methyl group attachment can be attached to the left or the right side of the side chain. These two variations of amphetamine are mirror-image racemic forms or stereoisomers. When the methyl group is on the left side of the side chain the compound is called L-amphetamine or levoamphetamine or the levo-isomer. When the methyl group is on the right side, the compound is D-amphetamine or dextro-amphetamine. D-amphetamine has greater biological activity than the L-form. The first amphetamine compound, Benzedrine sulfate, contained a mixture of D and L amphetamine forms. Adderall is also a mixture containing 4 different amphetamine salts comprised of about 72 percent D-amphetamine.
Drugs are chemicals either derived from plant phytochemicals or synthesized. Stimulants are drugs that tap into the brain’s communication system. Specifically, stimulants interfere with the way nerve cells (neurons) send, receive, and process information. Stimulants have a chemical structure that allows them to alter levels of various brain chemicals that target the body’s reward center. In particular, stimulants raise levels of the neurotransmitter dopamine. Dopamine affects movement, emotions, cognition, motivation, and feelings of pleasure. The increased brain stimulation related to amphetamines can cause feelings of euphoria. People who abuse drugs occasionally seek the euphoric effects attributed to amphetamines. This craving for euphoria is considered the root cause of the abuse potential of psychostimulant drugs (National Institute on Drug Abuse 2008).
Psychostimulants are chemical compounds that primarily work by stimulating the central nervous system and reducing fatigue. Although these facts constitute nearly all that was known about amphetamines in the 1930s, it’s now known that psychostimulant drugs cause important changes in the brain, and they raise levels of various brain chemicals. These are the effects that make amphetamine an important therapy in attention deficit hyperactivity disorders and depression.
Often referred to as “uppers,” psychostimulants include caffeine and a variety of plant herbs, such as Catha edulis (khat), guarana, Ephedra species, amphetamines and amphetamine-like drugs (amphetamine congeners), and the cacao pod plant. From a chemical viewpoint, amphetamines belong to a broad class of chemicals known as sympathomimetic amines, which have amphetamine as their prototype drug. While both nicotine and caffeine have properties that lead to their routine classification as psychostimulant substances, they do not enhance locomotor behavior in rodents the way amphetamines and cocaine do. Thus, from a strict pharmacological standpoint, nicotine and caffeine are not considered psychostimulant drugs.
The untoward physiological effects of caffeine are described in this section, and the effects of sympathomimetic amines are described later in this chapter and in Chapters Two and Eight. Adverse effects of caffeine include agitation, irritability, headache, restlessness, insomnia, delirium, hallucinations, vasodilation, angina, flushing, palpitations, sinus tachycardia, gastritis, and vasodilation (Pohler 2010). Other psychostimulants can cause similar adverse effects. Adverse effects of caffeine and other drugs can occur as idiosyncratic reactions due to genetic influences on drug metabolism or they can occur as a result of drug doses that are too high or toxic for an individual.
In addition to its stimulant effects, caffeine meets all the requirements for being an addictive substance, including its ability to cause dependence, tolerance, and withdrawal. A syndrome known as caffeinism can result from chronic caffeine consumption. Symptoms of caffeinism include nervous irritability, tremulousness, muscle twitching, sensory disturbances, tachypnea (rapid breathing), generalized anxiety or depression, palpitations, flushing, arrhythmias, diuresis, and gastrointestinal disturbances. Caffeine withdrawal symptoms can occur within 12–24 hours after termination of caffeine and include headache, irritability, fatigue, dysphoric mood, difficulty concentrating, decreased cognitive performance, muscle aches, and stiffness (Pohler 2010).
For thousands of years, plant products containing amphetamines or amphetamine-like compounds have been used for their stimulating effects. The most popular plants used are Ephedra species and leaves from the tree Catha edulis, known in Arabic and Swahili as khat (qat) and throughout East Africa as myrrah (miraa).
Ephedra sinica, which is known as ephedra and in China as Ma huang (meaning “looking for trouble”), has been located in burial sites in the Middle East and in Vedic temples in India. A first century AD book of Chinese herbal medicine, Shen Nong Ben, refers to ephedra as a treatment for asthma and upper respiratory infections (Sulter et al., 2005). Over-the-counter ephedrine has been widely used as an appetite suppressant and to boost athletic performance. In 2003 it was implicated in the death of Baltimore Oriole pitcher Steve Bechler, and in 2004 its used as a dietary supplement in America was banned by the Food and Drug Administration (http://www.fda.gov/NewsEvents/Testimony/ucm115044.htm accessed Nov. 22, 2009).
Fresh leaves of Catha edulis, which is native to Kenya and Somalia, represent 30 percent of the agricultural crops in Yemen. The active ingredients in khat include the amphetamines cathinone and norpseudoephedrine (cathine). The clinical uses of khat were described in the 11th century in the book Pharmacy and Therapeutic Art. Users of khat chew the stems or leaves, and in many homes in Yemen, a separate room is reserved for khat-chewing. Khat causes gregariousness, feelings of contentment, reduction of fatigue, and appetite loss. Khat is known to cause paranoia, toxic psychosis, drug dependence and other behavioral disturbances. Other reported acute and chronic effects of khat include low birth weight in babies of khat chewing women, reduced sperm count and motility, increased risk of myocardial infarction and liver disease. With international travel, khat has spread to other regions of the world. Khat is now under national control in Africa, Asia, Europe, and North America, where khat is a Schedule I controlled substance. In 2003, the World Health Organization considered that there was sufficient information on khat to justify a critical review (World Health Organization 2003).
Other plants containing amphetamine-like compounds include Citrus aurantium (bitter orange), Egyptian jasmine, the betel nut, Acacia berlandieri, Acacia rididula Benth (blackbrush), and mescaline. Mescaline is derived from dried tops of the peyote cactus Lophophora williamsii and related species.
Based on their neurochemical properties, amphetamines have been assigned to a large family of related compounds known as sympathomimetic amines. Like most family members, the drugs in this family share a number of similar properties, particularly their ability to increase brain levels of the neurotransmitter (chemical messenger) dopamine.
The class of drugs known as sympathomimetic amines was first described by British pharmacologists George Barger and Henry Hallett Dale in 1910 (Goodman and Gilman 1955, 476–7). The drugs belonging to this family share some basic structural features, in that they contain one benzene ring attached to two carbon atoms and an amine group (NH2). Slight substitutions can be made to the ring structure, to the carbons, or to the amino group that result in different compounds. For example, methylphenidate (Ritalin) has a chemical structure very similar to that of amphetamine.
However, their structural similarity is not what unites them. Besides having chemical skeletons that look similar, drugs in this family act in a similar biochemical fashion. All of the sympathomimetic amines stimulate the sympathetic nervous system, causing effects similar to those caused by a rush of adrenaline. Like most family members, the individual sympathomimetic amines differ slightly from one another in their characteristics. These differences include variations in the potency and specific organ and nervous system effects. For instance, methamphetamine stimulates the nervous system to a greater degree than amphetamine.
Sympathomimetic amines owe their property of stimulating the nervous system to their ability to react with the sympathetic terminal of nerves. That is, drugs in this group stimulate the nerves of the sympathomimetic nervous system. In doing so, these drugs can react either directly with the nerve or they can react indirectly by stimulating production and release of the brain’s messenger chemicals known as catecholamines. By increasing catecholamine levels, amphetamines send a command to neurons that improve attention, focus, and well-being.
Sympathomimetic amines include epinephrine (adrenaline), the major active hormone secreted by the adrenal glands, and a number of synthetic drugs, such as amphetamine, pseudoephedrine, and methamphetamine and also a variety of plant compounds such as khat. Synthetic (manufactured) sympathomimetic amines were developed in an effort to produce drugs that could mimic the actions of the hormone epinephrine, the hormone that drives the fight or flight response. The first drug in this class to be commercially developed was Adrenalin, which quickly became immensely popular for its benefits in surgery and for improving respiration in patients with breathing disorders. Because amphetamine is the prototype (sort of a role model) synthetic sympathomimetic amine, drugs of this class other than amphetamine and methamphetamine are often referred to as amphetamine or amphetamine-like compounds or amphetamine congeners.
The effects of amphetamine-like compounds largely stem from their influences on a class of naturally occurring (endogenous) chemicals known as neurotransmitters. Neurotransmitters are natural chemicals found in the body that facilitate the transmission of signals from one neuron (central nervous system cell) to other neurons or to other cells. These signals travel across connective junctions known as synapses. Neurotransmitters such as dopamine and acetylcholine relay, amplify, and modulate these cellular signals.
Neurotransmitters are also stored in synaptic vesicles found on the pre-synaptic side of a synapse. By being stored on cell membranes the neurotransmitters are available to be used as needed. Once released into the synaptic cleft, neurotransmitters bind to protein receptors in the neuronal membrane on the post-synaptic side of the synapse. By binding to the appropriate cell receptor, the message is delivered and the chemical order is initiated. Besides dopamine and acetylcholine, neurotransmitters include norepinephrine, glutamate, serotonin, gamma-aminobutyric acid (GABA), and endorphins.
Amphetamine and closely related compounds, including methamphetamine, methyphenidate (Ritalin), methylenedioxymethamphetamine (ecstacy), khat and Ephedra belong to the only class of drugs that predominantly work by increasing the brain and nervous system’s supply of neurotransmitters. Amphetamine and its chemical cousins primarily increase levels of the neurotransmitters dopamine and norepinephrine.
This ability to raise neurotransmitter levels in the brain make drugs of this class not only unique, but it provides them with many therapeutic benefits such as the ability to raise blood pressure in individuals with hypotension (pressor effect), increase respiration and relieve symptoms in asthma, alleviate symptoms of depression, inhibit drowsiness in narcolepsy, improve concentration and reduce hyperactivity in attention deficit hyperactivity disorder (ADHD), act as an anorectic (weight loss) agent in obesity, and enhance performance in situations of fatigue. The role of amphetamines in ADHD is described further in Chapter Four, and the effects of amphetamines on performance are explained in Chapter Five.
By comparing their chemical properties and classifying chemicals of this category together in 1910, Barger and Dale prompted researchers to develop other compounds related to epinephrine. This line of research ultimately led to the development of amphetamines. As early as 1910, researchers had determined that drugs in the sympathomimetic amine family, while resembling each other, had their own unique properties and pharmacological actions.
Writing in 1955, Goodman and Gilman explain, “Some compounds which Barger and Dale investigated have only recently created interest.” They were referring to the fact that in 1955 both amphetamine and methamphetamine had in the past twenty years received FDA approval (Goodman and Gilman 1955, 517, 533). In addition, between 1955 and 2010 more than twenty other amphetamine-like compounds had been approved, although some of them, like fenfluramine (the fen in the diet drug combination fen-phen), had come and gone.
Catecholamines are chemical compounds with epinephrine as their prototype or role model. Like the sympathomimetic amines, catecholamines are direct acting, indirect acting, or mixed acting sympathomimetic agents. Direct acting compounds react directly with one or more of the adrenergic receptors to stimulate the central nervous system, whereas indirect acting drugs increase the availability of neurotransmitters such as epinephrine or dopamine to stimulate adrenergic receptors. This indirect effect is accomplished by the chemical’s ability to block transport mechanisms or metabolic enzymes. Amphetamine and cocaine are both indirect acting. Catecholamines normally only have a brief duration of action, and they’re ineffective when administered orally. Drugs like amphetamine and other oral sympathomimetic amines are effective because of their ability to release neurotransmitters.
The physiological effects of amphetamine are primarily related to their ability to increase levels of catecholamine neurotransmitters. Catecholamines are chemical neurotransmitters produced in the chromaffin cells of the adrenal medulla and the postganglionic fibers of the sympathetic nervous system. Catecholamines are spontaneously released by the adrenal glands in response to physical and psychological stress (fight or flight response). Structurally, catecholamines contain a catechol group, and they’re derived from the amino acids tyrosine and phenylalanine. Catecholamines include the neurotransmitters epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine.
The primary reason for amphetamine’s favorable effects is the increase in dopamine levels that it elicits, although some effects are related to increases in norepinephrine. Overall, amphetamine influences cerebral circuits in the prefrontal cortex, basal ganglia and cerebellum. These brain components are associated with motivation, reward, executive functioning and motor coordination. With increased levels of dopamine and norepinephrine, amphetamine fine-tunes an individual’s ability to focus and pay attention.
Amphetamines are able to increase catecholamine levels via an indirect reaction. Rather than causing increased production of catecholamines, amphetamines inhibit their natural degradation. Once released into the blood circulation, catecholamines only last for a few minutes before they’re metabolized or degraded. Catecholamines are broken down either by a process of methylation by the enzyme catechol-O-methyltransferase or losing an amine group (deamination) by monoamine oxidase (MAO) enzymes. Amphetamine increases dopamine concentrations by inhibiting the action of MAO enzymes. Thus, dopamine levels are increased for longer periods, and the effects caused by amphetamine are longer lasting than those of cocaine and other psychostimulants.
Besides raising levels of catecholamine neurotransmitters in the brain, amphetamine stimulates the release of norepinephrine from nerve terminals in the sympathetic nervous system. The sympathetic nervous system controls heart rate, blood pressure, gut movement and various endocrine functions.
The actions of sympathomimetic amines and catecholamines can be classified into seven major types that explain some of the characteristic symptoms caused by these compounds such as palpitations, dry mouth, weight loss, and increased sweating:
1. a peripheral excitatory action on certain smooth muscle, for instance the tissue in blood vessels that supply the skin, kidney, and mucous membranes, and on gland cells, for instance those in salivary glands and sweat glands;
2. peripheral inhibition on certain other types of smooth muscle, for instance tissue in the wall of the gut, the bronchial tree, and in the blood vessels that supply skeletal muscle;
3. an excitatory action on heart muscle that increases both the heart rate and the force of contraction;
4. various metabolic actions, for instance an increased rate of glucose breakdown in liver and muscle and the release of free fatty acids from adipose tissue;
5. endocrine actions such as the modulation or balancing of the secretion of insulin, renin, and pituitary hormones;
6. central nervous system actions such as respiratory stimulation, increase in wakefulness and psychomotor activity, and a reduction in appetite; and
7. actions involving neurotransmitters, both inhibitory actions and those that involve the release of neurotransmitters (Westfall and Westfall, 2006).
Not all of the compounds in these drug classes show each of these actions to the same degree, and this is what explains their different pharmacological actions.
Neurons in different parts of the brain have different functions. For instance, an area of the cerebral cortex called the primary sensory cortex communicates with the sense organs. Messages can then be sent to areas of the cortex involved in perception and memory. Neurons communicate with each other through a highly specialized, precise and rapid method. The action potential is a brief electrical impulse that travels along the body or axon of the neuron. This allows one neuron to communicate with another through the release of as signaling chemical known as a neurotransmitter. Action potentials allow a message to be propagated along an axon within one neuron.
However, for communication to be complete, this message must be transmitted between neurons. This is accomplished at the synapses or connecting spaces at the terminal buttons (at the end of the nerve cell) through the release of neurotransmitter. After being released from neurons, neurotransmitters interact with receptors or lock on other neurons. By activating the neuron’s receptor, the neurotransmitter affects a specific change in that neuron, for instance causing biochemical changes that lead to increased alertness.
Dopamine is a neurotransmitter that the body produces from the amino acid tyrosine. The brain has two major dopamine pathways: the mesolimbic-mesocortical pathway that is activated by most psychoactive substances and the nigrostriational pathway that projects from the substantia nigra to the striatum. Excessive dopamine function in the mesolimbic-mesocortical dopamine system is thought to underlie the delusions and hallucinations of schizophrenia. Depending on the psychostimulant used, increases in dopamine can affect either of two different areas of the brain related to drug dependence: the ventral tegmental area (VTA), and a region that it communicates with, known as the nucleus accumbens. In high doses, amphetamine can mimic schizophrenia and bipolar disorders through the same type of basic actions causing excess neurotransmitter release that are exerted on the dopamine system in these disorders (World Health Organization 2004).
The ability of amphetamine to raise dopamine levels is responsible for the majority of its desirable effects. Dopamine is a central neurotransmitter with particular importance in the regulation of movement and with reward mechanisms in the brain. Dopamine increases feelings of well-being. Low dopamine levels are associated with social anxiety, difficulties with focus and concentration, depression, and a variety of conditions related to a depressive form of low energy called anergia.
The adrenal hormone epinephrine (adrenaline) is a potent stimulant. Because it activates both alpha and beta-adrenergic receptors, it has complex effects on multiple target organs. Epinephrine quickly elevates blood pressure by a mechanism in which it strengthens heart contractions, increases heart rate, and constricts blood vessels. In situations of bleeding, such as trauma or surgery, epinephrine markedly decreases cutaneous blood flow while increasing blood flow to skeletal muscles. Epinephrine relaxes bronchial muscle, making it an excellent therapy for conditions in which the bronchioles are constricted, such as asthma. Rather than stimulate the nervous system directly, epinephrine’s effects are secondary to its effects on the cardiovascular system. Thus, epinephrine may cause tremor, restlessness, throbbing headache, and palpitations.
Norepinephrine (levarterenol, l-noradrenaline) is a major chemical neurotransmitter found in the postganglionic sympathetic nerves. Norepinephrine is similar to epinephrine except for its actions on adrenergic receptors. Norepinephrine is potent when it comes to activating alpha-receptors, although less potent than epinephrine, and it has a milder action on beta-receptors. Norepinephrine raises both systolic and diastolic blood pressure to levels higher than those caused by epinephrine. In addition, it increases coronary blood flow while constricting skeletal muscle. Norepinephrine has limited therapeutic value, and it is primarily increased in conditions of shock (Goodman and Gilman 2006).
In 1901 the Johns Hopkins University researchers J. J. Abel and Jokichi Takamine first developed an injectable form of the adrenal hormone epinephrine, which they patented as Adrenalin. It didn’t take long for physicians worldwide to appreciate epinephrine’s tremendous applications in medicine and for research chemists to envy its commercial success. Consequently, a bevy of American chemists began a quest to synthesize other hormones as well as chemicals that could be used as oral stimulants. Such early research led to the development of synthetic insulin, and it initiated a novel working collaboration between universities and pharmaceutical companies that has proven mutually beneficial through the years.
Twenty years after the discovery of Adrenalin, as part of his employment developing allergy extracts, the chemist Gordon Alles learned of the stimulant effects of ephedrine, a compound from the Chinese herb Ephedra. Alles’s employer, George Piness, the owner of a research laboratory in Los Angeles, asked Alles to look for other sympathomimetic amines with properties similar to those of ephedrine (Grinspoon and Hedblom 1975, 43). Because of its ability to stimulate the respiratory system, ephedrine was considered a primary therapy for asthmatics and a profitable drug. Intrigued by its other stimulating effects, Alles focused on creating structurally similar chemicals.
By 1930 Alles concluded that there were no compounds superior to amphetamine, which was first synthesized in 1887 by the Romanian chemist Lazar Edeleanu (Edeleano). Edeleanu’s compound was called amphetamine as a contraction of its generic name, alpha-methyl-phenylethyl-amine. Alles and Piness were familiar with Edeleanu’s work, which had been published in chemical journals.
Although Edeleanu wrote his doctoral dissertation at the University of Berlin on amphetamine, he hadn’t discovered its physiological properties. In 1928, Alles also synthesized amphetamine, which he called beta-phenylisopropylamine. This chemical name is still used for amphetamine. Alles quickly received patents for both L-amphetamine and D-amphetamine salts, and he received the first patent for amphetamine’s medical use.
By 1928 amphetamines had also been synthesized by Japanese researchers. However, while Alles wasn’t the first scientist to synthesize amphetamine, he was the first to realize in commercial terms just what his discovery meant. Alles approached the pharmaceutical company Smith, Kline and French (SKF) about using his amphetamine salts. Using an identical amphetamine chemical in a volatile form discovered and patented by the chemist Fred Nabenhauer, SKF had introduced the first patent form of Benzedrine in 1932 as an over-the-counter inhaler. The volatile amphetamine oil was imbedded onto a folded cotton strip pressed inside a plastic case called the Benzedrine inhaler. As a nasal inhaler, Benzedrine was effective for relieving sinus conditions, although its stimulating effects are what led to its sudden popularity. Before long, some people began removing the embedded Benzedrine, which contained as much as 560 mg of volatile oil, and chewing the cotton strips.
In 1936, using amphetamine salts developed by Alles and calling the product Benzedrine Sulfate to match the Benzedrine inhaler’s name, Smith, Kline and French began to sell amphetamine in 10 mg tablets, which were also available without a prescription. Since then, many similar chemicals, such as methamphetamine and methylphenidate, have been developed and the medical uses and abuses for these pharmaceutical compounds have grown as well. These uses and abuses are described further in Chapter Two.
Despite its obvious biochemical properties, amphetamine was initially a drug looking for a disease. Without the rigid restrictions of today, at the time of its release, Smith, Kline and French offered amphetamine free to any physicians willing to use it. Without clinical trials, patients’ anecdotal accounts were used to determine the drug’s efficacy.
As part of his research, Alles tested the new synthetic compounds he was synthesizing on dogs and rabbits at the University of California’s physiology department. He used anesthetized animals and observed any changes in blood pressure. He found that amphetamine, like ephedrine, raised blood pressure when administered orally, although amphetamines had a longer lasting effect. Extrapolating from the doses used in animals, in June 1929, Alles had a friend inject him with 50 mg of amphetamine (Rasmussen 2008a, 15). Such self-experimentation was a common practice among medical researchers and considered necessary at that time. Today, it’s known that a drug’s inventor shows natural bias and confidence regarding its safety. Consequently, best practice today calls for an independent review before anyone attempts a human experiment.
On that June day in 1929, Alles noticed a feeling of well-being and a brief palpitation. As a result of his experiment and the earlier animal studies, Alles considered amphetamine safe. Two days later, Alles and Piness, the allergist he worked for, administered 20 mg of amphetamine orally to a patient having an asthma attack. Like Alles, this patient reported feeling exhilarated and observed palpitations. With no evident asthma relief from amphetamine after two hours, the allergist administered adrenaline. One week later, Alles and Piness administered 50 mg amphetamine by injection to this same patient during an asthma attack. Her pulse rose from 106 beats per minute to 180, and her blood pressure rose nearly 50 percent. The patient’s wheezing improved but she developed a violent headache and nausea. Piness and Alles repeated this experiment on two more patients and concluded that amphetamine might work as a decongestant in nasal drops but was of limited value in asthma. Alles presented these findings at the West Coast American Medical Association (AMA) meeting in Portland, Oregon, in the autumn of 1929.
In January 1930, Alles and three friends began to experiment with lower daily doses of amphetamine. They recorded their pulses and blood pressure readings periodically and noted their other impressions. Little effect on pulse and blood pressure was noted. However, three of the subjects reported insomnia or restlessness at least on one night, three reported feeling jumpy or experienced trembling, and all four subjects reported feeling exhilarated or peppy. Other reports included an improvement in sinus congestion. In September 1930, Alles applied for a patent application on the oral use of amphetamine salts. In 1934, fearing Edeleanu might dispute his patent, Alles submitted a disclaimer with the patent office, claiming medical uses for his invention.
After inventing amphetamine, Alles continued researching a better oral drug for asthma. His experiments led to the discovery of the chemical known as methylene-dioxyamphetamine (MDA), one of the two chemicals now known as ecstacy, and hydroxyamphetamine (Paredrine). Alles never discovered the asthma drug he was looking for, and as he continued his research he sought out medical uses for amphetamine. To make any profit on his invention, it needed a use.
People affected with narcolepsy fall deeply asleep during the day without warning. Because ephedrine had been reported to help people with this disorder, Alles gave some amphetamine to a physician friend, Myron Prinzmetal, to try on patients with narcolepsy.
In addition, Alles gave the California physician Morris Nathanson amphetamine to evaluate as a heart stimulant in patients with diminished cardiac function and to Michael Leventhal, a Chicago gynecologist, to try on patients with dysmenorrhea, a disorder of painful menstruation. Reports suggest that amphetamine offered promise in these conditions and also in Parkinson’s disease. However, even though amphetamines benefited patients with various conditions such as these, they weren’t considered profitable enough to list as amphetamine’s main use.
Ecstasy tablets (MDA, MDMA) (homeoffice.gov.uk).
Nathanson’s study, which was published in 1937, involved doses of 20 mg Benzedrine given orally to 55 young hospital workers. The employees overwhelmingly reported a sense of well-being and a feeling of exhilaration as well as lessened fatigue in reaction to work. Many employees also noted weight loss, which researchers initially attributed to the subjects’ feeling better and their ability to take on more tasks.
Numerous reports and publications confirm that SKF’s efforts in supplying physicians with Benzedrine tablets to evaluate in various medical conditions paid off. In addition to providing Benzedrine at no charge, SKF commissioned a number of experts to research the use of amphetamines in specific conditions. A study conducted at the University of Pennsylvania medical school by the internist Wallace Dyer evaluated the effects of increasingly higher doses of amphetamine on blood pressure. Although a similar study today wouldn’t be ethical because it involved subjects with high blood pressure who could have sustained harm, this study demonstrated that the drug could be safely used.
After receiving his samples, the Harvard psychiatrist Abraham Myerson became an early champion of amphetamine and reported that it helped his mood as well as his lecturing. He found that his inpatients also showed improvements in mood, and he discovered that amphetamine could be used to help counter the effects of barbiturates. Myerson was an eminent researcher as well as a known intellectual with interests in politics and social welfare. Myerson was also an expert on depression and in 1925 wrote a book called When Life Loses its Zest. At the April 1936 Boston meeting of the AMA, Myerson described the amazing benefits offered by amphetamine for patients with depression, particularly depression with characteristics of anhedonia. In anhedonia, individuals find little in life that makes them happy or joyful (Rasmussen 2008a, 33–4).
Myerson’s observations and studies of amphetamine at the Mayo Clinic in Minnesota both suggested that amphetamine relieved depression. Studies showing improvement in psychiatric patients at Bellevue Hospital in New York City and at state facilities in Colorado and Illinois also found their way into medical journals, and amphetamine’s use as an effective treatment for neurasthenic depression gave it a legitimate entry into conventional medicine. In early 1937, SKF created a circular describing current research and stating that the primary medical use for amphetamine was in improving mood.
An early medical journal advertisement for Benzedrine.
The 1910 studies on sympathomimetic amines by Barger and Dale also helped establish amphetamine’s role as a psychiatric drug. With a simple explanation of its effects on brain chemistry and numerous reports praising its benefits, in the early 1930s amphetamine became a major therapy in the fight against depression.
Other than listed narcotics, pharmaceuticals were largely unregulated in 1935. The AMA Council on Pharmacy merely required manufacturers to provide scientific evidence that a new drug was effective for the disorders claimed and that it was safe in recommended doses before they approved its advertising in participating medical journals. Beginning in 1901, as long as a drug was deemed safe in animals, it could be tested in human subjects as long as the subjects gave consent and were given reasonable information about the drug (Lederer 1995, 2).
In December 1937, after reviewing Myerson’s study and related publications, the AMA Council on Pharmacy approved the advertising of amphetamine for narcolepsy and Parkinson’s disease, and also as a remedy for mood elevation in depression and other psychiatric conditions. Similar to today’s off-label use of drugs, physicians could use amphetamines for any disorders they felt it might help.
By then, following experiments by the University of Minnesota Department of Psychology that showed amphetamine improved alertness, its popularity had grown immensely. Between 1936 and 1939, over 50 million Benzedrine tablets were sold in the United States. With changes to drug policies, on January 1, 1939, Benzedrine required a prescription. With prescriptions easy to acquire, drug sales continued to soar.
By 1935, abuse of the Benzedrine inhaler led to the AMA’s recommendation that the inhaler contain a sticker warning “Do Not Overdose.” Amphetamine’s potential for addiction was mentioned as early as 1937, and two cases of psychosis suspected of being induced by amphetamine in patients being treated for narcolepsy were reported in 1938. However, it wasn’t until the mid 1960s that the full addictive potential and the development of amphetamine psychosis were fully recognized. In 1938, the cases of amphetamine psychosis were naively attributed to latent psychiatric disorders.
Reports of amphetamine being abused by dieters also emerged in 1938, although amphetamines hadn’t yet been approved as diet aids. As a treatment for alcoholism, amphetamines appeared to be replacing alcohol as the drug of choice and early on were associated with reports of amphetamine psychosis. In 1939, a 25-year-old Purdue University student who had regularly been taking 5 mg Benzedrine “brain tablets” before examinations collapsed and died during an examination. The student was reported to be a good athlete and was thought to have ingested about 30 mg of Benzedrine in the few days before his death, with 10 mg ingested on the day of the exam. Autopsy findings revealed dilation of the right auricle of the heart and gastric and splenic dilation (Rasmussen 2008a, 50; Grinspoon and Hedblom 1975, 136). These and similar problems created marketing problems for SKF. Although there were reports of amphetamines offering benefits to children with learning disabilities as early as 1936, SKF decided to forego that line of research and focus on marketing amphetamines for depression.
Despite a rising increase in adverse publicity and growing reports of potential addiction, Americans continued their love affair with amphetamine. Students, professors, artists, musicians, medical personnel, truck drivers, athletes, writers, and actors became some of amphetamine’s biggest fans. But some of the most widespread and controversial uses of amphetamine compounds can be found among military personnel. The use of amphetamines in the military and the tremendous research on amphetamines carried out by the armed forces is described in Chapter Two.
Soon after amphetamine hit the market, many people discovered that they liked its psychostimulant effects. People who tried amphetamines reported that it made them feel more alert and more energetic, which is why amphetamine soon became known as “speed.” Side effects when used at recommended doses were mild and included a slight elevation of heart rate and blood pressure that resolved within a few weeks of therapy, nervousness and insomnia.
Amphetamine affects smooth muscles, the central nervous system and psychic state. High doses bring about toxic effects in the form of exaggerated responses. Psychosis and other disturbances have been documented from amphetamine use, as have incidents of death.
Administered orally, amphetamine raises both systolic and diastolic blood pressure and reflexively lowers heart rate, although significant increases aren’t usually observed when low doses (less than 20 mg daily of D-amphetamine) are used. With large doses, cardiac arrhythmias may occur. L-amphetamine is slightly more potent than D-amphetamine in its cardiovascular actions.
Smooth muscles typically respond to amphetamines similarly to the actions seen with other sympathomimetic amines. Amphetamine has a marked contractile effect on the sphincter of the urinary bladder, which makes it an effective treatment for enuresis and incontinence. Gastrointestinal effects of amphetamine are less predictable. When enteric activity is pronounced, amphetamines may relax and delay bowel movements, causing constipation, whereas if the gut is already relaxed, bowel movement may increase (Westfall and Westfall 2006, 237–95).
Of the sympathomimetic amines, amphetamine is one of the most potent when it comes to its ability to stimulate the central nervous system (CNS). It stimulates the medullary respiratory center and lessens the degree of central depression caused by barbiturates and other CNS depressants. Regarding its CNS effects, D-amphetamine is 3 to 4 times more potent than L-amphetamine.
Psychic effects are dependent on the dose and the mental state and personality of the individual. Most oral doses between 10 and 30 mg cause wakefulness, alertness, decreased fatigue, mood elevation, increased initiative and self-confidence, and improved powers of concentration. Elation and euphoria can also occur and an increase in speech and motor activities is common. Performance of simple mental tasks is improved, but although the amount of work may be higher, the accuracy of the work may be lower. Performance enhancement is described further in Chapters Four and Five.
Amphetamines have long been used as weight loss agents, although the wisdom of this use is controversial because weight loss is seldom sustained after the drug is stopped. Weight loss caused by amphetamines is almost entirely a result of reduced food intake and only partially due to an increased metabolism. There may be other reasons for weight loss related to increased dopamine and norepinephrine levels, but the mechanisms supporting this are unclear.
The amphetamine drug dose that causes toxicity is highly variable. In individuals who develop idiosyncratic reactions to amphetamine, toxicity can occur with doses as low as 2 mg, although toxic reactions are rarely seen in doses lower than 15 mg. Severe reactions have been reported in doses of 30 mg, although doses as high as 400–500 mg are not uniformly associated with mortality. With chronic use of the drug, higher doses can be tolerated (Westfall and Westfall 2006, 237–95).
The acute toxic effects caused by amphetamine are usually exaggerated responses of the drug’s therapeutic actions and result from excessively high drug dosages. Commonly observed CNS effects of high doses include restlessness, dizziness, tremor, hyperactive reflexes, talkativeness, tenseness, irritability, weakness, insomnia, fever, and occasionally euphoria. Other adverse effects that may occur but which are more likely to occur in mentally ill patients include confusion, aggressiveness, changes in libido, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or homicidal tendencies (Westfall and Westfall 2006, 237–95). These effects can also occur in chronic users of amphetamine. The stimulation caused by prolonged use of amphetamine is often followed by periods of fatigue and depression.
Cardiovascular effects caused by high doses or chronic amphetamine ingestion include headache, chilliness, skin changes such as pallor or flushing, palpitation, cardiac arrhythmias, angina, hypertension, hypotension, excessive sweating, and circulatory collapse. Gastrointestinal effects include dry mouth, metallic taste, nausea, vomiting, anorexia, diarrhea, and abdominal cramps. Amphetamine toxicity and adverse effects are also described in Chapters Two and Eight.
Since the first amphetamine death reported in 1938, there have been deaths reported each year that are associated with amphetamines. Toxicity occurs when high amphetamine doses markedly increase its peripheral cardiovascular effects. D-amphetamine has a greater potential than D-methamphetamine to affect the cardiovascular system, although D-methamphetamine is a greater central nervous system stimulant. In general, acute fatal drug reactions to amphetamine are more common in the occasional user than in the tolerant, chronic, high-dose abuser (Ellinwood 2000, 3). Manifestations of acute overdosage with amphetamines include restlessness, tremor, hyperreflexia, rapid respiration, confusion, aggressiveness, assaultiveness, hallucinations, panic states, hyperpyrexia (elevated body temperature) and rhabdomyolysis (muscle breakdown).
Most of the amphetamine-related deaths that have been reported are due to excessive stimulation of heart and a quick rise in blood pressure, leading to stroke (cerebral hemorrhage) or heart failure. Fatal overdoses usually progress to convulsions and coma. Stroke in these cases is primarily related to damage and bleeding in the blood vessels of the brain. Damage to the blood vessels of the brain is the most common pathological finding on autopsy (Iversen 2008, 13).
Amphetamines can raise the body temperature, and hyperthermia is suspected of contributing to the deaths in several athletes using moderate doses of amphetamines in the 1960s and 1970s. The majority of cases of cardiovascular collapse secondary to ventricular fibrillation have occurred in individuals less than 30 years old with no evidence of pre-existing heart disease (Ellinwood 2000, 3). Other miscellaneous causes of amphetamine related deaths include septicemia with bacterial endocarditis or necrotizing angiitis occurring primarily in intravenous drug users.
Shortly after Benzedrine’s introduction in the 1930s, rare reports of psychotic reactions to both the inhalers and the tablets began to emerge. Symptoms of amphetamine psychosis are similar to those of paranoid psychosis and include auditory, tactile, and visual hallucinations accompanied by agitation, panic, hyperactivity and excitement. These symptoms are seen in patients who appear to have clear consciousness and a relatively intact mental status that happens to be interrupted by delusions and hallucinations that can invoke intense fear. Amphetamine psychosis is caused by repeated intoxication. This term doesn’t apply to the acute clinical picture characterized by delirium and confusion that follows an acute large dose of a central nervous system stimulant (Bayer 2000, 62).
In his excellent book On Speed, Nicholas Rasmussen describes several case reports of individuals who developed amphetamine psychosis. In one instance, a forty-nine-year-old lawyer ended up in a Massachusetts mental facility insisting that six cars were regularly trailing him, and that his son who was serving in the military communicated with him from an invisible helicopter that was flying overhead. If that wasn’t enough, he was certain that the government was spying on him to test his loyalty for a highly secretive mission. This man had been taking Benzedrine tablets for five years, which successfully helped him with a drinking problem. However, he had gradually increased his dose to more than ten times the recommended amount for a total intake of 250 mg daily (Rasmussen 2008a, 139).
In 1958, the U.K. psychiatrist P. H. Connell of the Maudsley Hospital published a report describing 42 patients he’d treated for amphetamine psychosis and described other cases he’d reviewed in the medical literature. He found amphetamine psychosis to be more common than initially thought and according to his case reports, symptoms typically resolved within a week of stopping the drug. These findings were confirmed in the United States in the Haight-Ashbury district of San Francisco in the 1960s. Since the 1960s, amphetamine psychosis is more readily recognized and its effects on brain chemistry are better understood. Amphetamine psychosis is also more common when amphetamine is injected, a common practice in 1960s Haight-Ashbury.
Appetrol (dextroamphetamine and meprobamate) in a medical journal advertisement.
By 1962, several new non-amphetamine drugs that had promised to be safer than amphetamines, such as phenmetrazine (Preludin) and phentermine (Ionamin) were also showing their abilities to cause dependence and amphetamine psychosis when used at high doses. Consequently, most of the amphetamine-like diet pills are as highly regulated as amphetamine.
In his chilling 1978 book Requiem for a Dream, Hubert Selby, Jr., describes a naïve widow and mother of a heroin addict who becomes hooked on amphetamines prescribed in high doses for weight loss. Depicting her fantasy life and wishful hallucinations, Selby describes her eventual plunge into amphetamine psychosis (1978). In the 2000 movie version of the book, Ellen Burstyn convincingly portrays life in 1970s Brooklyn and shows how the innocent use and abuse of amphetamines led to their eventual decline. Concern about the increased use of amphetamines and other stimulants led to a marked curtailment of their production and availability and eventual replacement by cocaine, considered by many in the 1970s to be a relatively benign drug (Goodwin and Guze 1994, 225).
The dopamine hypothesis is also supported by reports that even very small doses of stimulants that would not cause psychosis in individuals without schizophrenia can cause psychotic symptoms in individuals with schizophrenia (Ellinwood 2000, 12). This phenomenon is reported as being state-dependent and is most likely to occur in the active or unstable phases of schizophrenia or in previously undiagnosed patients. Because there is variability in the severity of schizophrenia, this phenomenon is more likely to occur in people with more severe degrees of schizophrenia. Symptoms of amphetamine psychosis in schizophrenia may be manifest as wildly bizarre behavior, catatonia, intense stereotyped behavior (see Chapter Two) and preservative self-stimulating behaviors.
Amphetamines can also cause a number of other psychiatric disturbances that are milder than those seen in amphetamine psychosis. These include stereotyped behavior, obsessive-compulsive behavior, and punding. These other psychopathologies are discussed in the following chapter.