Psychostimulants are psychotropic drugs that increase circulating levels of different neurotransmitters to generate arousal, counteract fatigue, and improve cognitive function (1-4). Amphetamines, cocaine, ecstasy, caffeine, and nicotine are among the most common psychostimulants, and each of these substances has been considered to have valid medical uses at some point in history (1-5). One of the main disorders for which doctors have prescribed psychostimulants is narcolepsy, a condition characterized by the inability to remain awake for extended periods of time (1,2,4-8). Other disorders that psychostimulants have historically been prescribed to treat include pain, depression, and even morphine addiction (1,5).
Of the psychostimulants, amphetamines and cocaine are particularly dangerous, alluring, and rich with history. Cocaine is illegal in the United States, although it is approved for medical use in some instances because of its anesthetic and vasoconstriction effects (8). Amphetamines also are medically approved in certain cases, and they are most commonly prescribed to people with Attention Deficit Disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD) (4,6,8). It is useful to evaluate amphetamines and cocaine together because they have very similar actions in the brain, and the two drugs attract similar users (1,5,6). Some examples of evidence of the similarities between amphetamines and cocaine include blind tests in which experienced drug users were unable to reliably distinguish between the two drugs. Furthermore, both drugs have similar patterns of modifications to neurotransmitter activity (9).
While both amphetamines and cocaine have some approved uses in medicine, they are very commonly used illicitly (1,7,11-16). These two psychostimulants in particular attract many recreational drug users because they are known to induce euphoria and greatly improve self-confidence (1,5,6). Amphetamines and cocaine achieve these effects by increasing circulating levels of dopamine (DA) and norepinephrine (NE), two neurotransmitters that are critically involved in the brain’s mesolimbic cortical DA pathway, also referred to as the reward pathway(1,5,9,10). The increased levels of DA in the reward pathway are most directly responsible for the euphoria that amphetamines and cocaine induce, while the increased levels of NE appear to be responsible for the drugs’ reinforcing effects (1,9,10).
Both cocaine and amphetamines come in a variety of forms, each of which has different properties (1). Pure cocaine looks like white powder and is associated with upper-class drug use (1,5). Free base cocaine is more commonly referred to as crack and is much less expensive (1). Crack comes in a crystalline form that varies in color from white to light brown, where whiteness is indicative of the purity of the substance (1). Crack is associated with lower-class drug use, and it is so named because of the cracking sound it makes when smoked (1).
Amphetamines have one methyl group, while methamphetamines have two methyl groups (1,5). However, this chemical distinction does not lead to significantly different behavioral effects among those who use these drugs (1,5). Methamphetamines metabolize into amphetamines, which accounts for the similar experiences elicited by the two drugs—both stimulate increased release of DA and NE. Methamphetamines induce similar feelings of euphoria and hypersexuality, but they are even more potent, addictive, and dangerous than amphetamines (14,17-19). The most common type of methamphetamine that is used recreationally is referred to as “crystal meth” and is incredibly stigmatized (1). Like amphetamines, it can be injected, snorted, or, most commonly, smoked (1). Methamphetamines do have some medically approved usage; Desoxyn is one methamphetamine that is approved to treat ADHD and is sometimes prescribed to help those struggling with obesity as a short-term solution (13,17). Methamphetamines are, however, extremely addictive and are prescribed only in extreme instances (13).
Cocaine is naturally derived from the Erythroxylon coca, a plant native to South America (1,5,11). Natives of the Andes have chewed leaves from this plant for centuries because of the plant’s energizing effect, which counteracts altitude sickness and improves mood (1,5,11). In 1855, Gaedcke, a German chemist, was the first to purify the Erythroxylon coca plant into cocaine (5). Cocaine had the same therapeutic effects as chewing the leaves, only with much greater potency (1,5,11). It was not long before cocaine caught the attention of the medical world (1,5).
Freud, the father of psychotherapy, was among the most prominent men in medicine to realize the tremendous potential that this drug could have in improving medicine (1,5). He was eager to make a name for himself, so he experimented with cocaine, using himself as a medical guinea pig (1,5). Freud was immediately impressed with cocaine’s miraculous ability to improve mood, alertness, and self-confidence, and he wrote a book to promote cocaine use: Uber-Coca (1,5). One of Freud’s most egregious claims was that cocaine should be administered to morphine addicts, an advice which he later retracted (1,5).
Freud was not the only prominent medical practitioner who fell victim to cocaine’s charm—soon after cocaine’s discovery the entire medical community raced to unlock its potential (1,5,6). The 1800s were a time before effective anesthetics had been discovered, and this meant that surgery was extremely limited (5). It was possible to put patients under general anesthesia, but anesthetics could cause patients to vomit, which interfered with more delicate procedures, such as eye surgeries (5). In 1884, Karl Koller, an Austrian ophthalmologist, published a successful account of injecting cocaine into a patient’s eye, thereby anesthetizing him sufficiently for eye surgery and bringing cocaine to the foreground of surgery and medical research as a promising local anesthetic (5,6).
Cocaine quickly gained approval from the medical community, but such a powerful and popular drug could not be contained solely within the medical world (1,5). Cocaine rapidly made its way out of surgery rooms and into soft drinks (1,5). Coca-Cola was so named for the plant from which cocaine is derived, and the beverage rose to economic success in large part because adding an addictive substance to a product brought customers back for more (1,5). In the early 1900s, children and adults alike were sipping on addictive Coca-Cola, lozenges were laced with cocaine that numbed sore throats, and advertisements boasted that bad moods need never happen again, since the golden age of cocaine had arrived (1,5).
Amphetamines were discovered three years following the first purification of cocaine (1,5,6). In 1887, another German chemist, Lazar Edelenau, was the first person to create an amphetamine (1). The chemist stumbled upon amphetamines in his quest to create a substance like ephedrine, which is a bronchodilator used to treat asthma (1). Amphetamines were found to have very similar effects to ephedrine, but it was Gordon Alles, an American chemist, who re-discovered and popularized amphetamines nearly thirty years after their first discovery (5).
Amphetamines were first commercialized as a replacement for ephedrine in the 1930s, and they were initially marketed as the Benzadrine Inhaler (1). The Benzadrine Inhaler was an instant success, and it was not long before amphetamines were marketed as a cure for narcolepsy, depression, post-partum depression, and Parkinson’s disease, along with a growing list of other conditions (1). During World War II, fighter pilots were administered amphetamines in order to stay awake for the entirety of their missions (1,5,6).
Amphetamines enjoyed a long period of medical approval, progressing from the treatment for asthma and depression to the cure for obesity (1,5,6). In the 1950s, amphetamines became a popular weight loss technique because they allowed people to lose weight effortlessly (1,5,6). Amphetamines came to be called “mother’s little helper,” both because they were handy appetite suppressants and because mothers could pop these pills in order to become peppier housewives (6). Housewives were not the only Americans under the influence—Andy Warhol was known to have enjoyed amphetamines, and even President Kennedy took amphetamine injections (6). In 1962, amphetamine use was so prevalent that there were eight billion amphetamine tablets circulating in America alone (6). Needless to say, addiction became a common problem in American households.
In 1957, Dr. P. H. Connell published a paper suggesting that amphetamine use likely led to psychosis (6). Up to that point, pharmaceutical companies had dismissed the accusations that amphetamines were causing psychosis, claiming that only those who had previously established symptoms of schizophrenia suffered psychosis (6). Connell’s paper demonstrated that amphetamine use was the most common factor among psychotic individuals (6). The connection between amphetamines and schizophrenia was further corroborated by the fact that even naturally occurring schizophrenia was caused by an excess of dopamine (6).
Psychosis is one of amphetamine’s most dramatic side effects, but cocaine and amphetamines both have many more downsides (1,5,6,17-24). High doses of either drug often lead to impaired judgment, impulsiveness, hypersexuality, and hypervigilance, as well as paranoia under the influence (1,2,5-7,24-26). These drugs also leave long lasting effects, including cognitive impairment, attention deficits, addiction, and diminishment of naturally occurring dopamine (DA) levels (22,26). In fact, amphetamine abuse has been shown to cause a 70% decrease in DA levels in some parts of the brain, and this decreased neurotransmitter production may be irreversible (2,22,26).
Cocaine and amphetamines fell from favor in the latter part of the twentieth century (27). In the 1960s, recreational drug use was so rampant that President Nixon based much of his domestic political platform on drug regulation (27). Some consider the 1970s to be a time of a “cocaine epidemic,” because South America began producing and selling the drug more cheaply than ever before (6,27). The U.S. Department of Health and Human Services estimated that more than one million Americans began cocaine use each year between the late 1970s and 1980s, and parents across America were terrified that their children would end up on the streets or in mental hospitals as a result of drug experimentation (11,27).
While many spent the Summer of Love in 1967 experimenting with LSD in San Francisco, Nixon was already six years into his war on drugs (27). Nixon’s campaign experienced its greatest success in 1970, when Congress passed the Comprehensive Drug Abuse Prevention and Control Act (27). This law categorized drugs into one of five schedules according to their potential for abuse and their medical potential, and this method of categorization persists today (27,28). Schedule I drugs are those which have “no currently accepted medical use and a high potential for abuse,” including heroin, LSD, and marijuana (28). Schedule II drugs are those which have a high danger of abuse, but also have some medical purpose (28). Both cocaine and amphetamines were put in this category in 1970, thereby marking the beginning of governmental regulation of the two psychostimulants (27).
While the Controlled Substances Act of 1970 dramatically reduced the availability of cocaine and amphetamines, there are still many Americans using the psychostimulants either illicitly or with prescriptions (11,27). There are very few instances in which doctors prescribe cocaine, such as sinus surgery and other procedures where cocaine might be necessary as a local anesthetic (8). There are safer anesthetics, and cocaine is considered as a last resort (8). Amphetamines, on the other hand, are still prescribed for a variety of conditions, including ADHD (for which Adderall is a commonly prescribed amphetamine), brain tumors, Parkinson’s disease, autism, and for fatigue associated with HIV (4,12,13,20).
Abuse and addiction are the two greatest problems with cocaine and amphetamines in modern America (20,26,28). One study in 2008 showed that three million Americans have illicitly used amphetamines within the past year, and that number is on the rise. The percentage of Americans who have used meth within the past month has stayed pretty consistently between 0.3 and 0.4 since 1999 (11,14). There were roughly 800,000 drug-related emergency room visits in 2008, and of those, 500,000 were due to cocaine (14).
It is currently estimated that 1.5 million Americans are dependent on cocaine, and between 250,000 and 350,000 Americans are estimated to suffer from an amphetamine addiction (6). A 2007 study revealed that 4.1 percent of tenth graders in America have tried meth at least once in their lives (6). Crystal meth is particularly well known for its addictive properties, and for the intensity of the addiction (29). Rehabilitation programs for crystal meth addicts have the lowest success rates of any drug rehabilitation programs. Only seven percent of patients remain clean following treatment.
The future of neuroscience as it pertains to amphetamines and cocaine lies in addiction research to improve the odds for addicts who seek treatment. Drug addiction, and illegal drug use in general, is intrinsically connected to violent crimes, both due to the illicit nature of drug smuggling, and because drug use itself can prompt people to rape, kill, and, in isolated but high profile instances, cannibalize (1,5,28). Drug use is an international problem; there are 24.7 million methamphetamine abusers internationally, and cocaine has an estimated 14-20 million users worldwide.
Addiction is defined as a craving for drugs so intense that it interferes with a person’s ability to function in daily life due to lasting changes that drugs make to the reward pathway in the brain (10,24,26,33,30). This pathway, the mesocorticolimbic dopamine system, can be thought of as a tug-of-war between the prefrontal cortex (PFC), which commands higher-order thinking, and the lower brain regions, which include the ventral tegmental area, amygdala, and striatum (10,22,26). While the PFC is active when a person exercises self-restraint, or focuses on a challenging mental task, the lower brain regions are responsible for drug cravings, fear response, and are recruited in the stress response (10,22,26).
In a normally functioning brain, the lower brain sends signals to the PFC, alerting it to run from dangerous situations and attend to similar animalistic, impulsive concerns (9,23,26). The difference between a well-functioning brain and that of an addict can be observed in the differing connection between the PFC and the lower brain. While a normal PFC is able to strong-arm the lower brain into taking the backseat, the PFC of many addicts is less able to dominate the lower brain (9,22,26). There is also evidence that those with overactive lower brain regions and otherwise normal PFCs are still at risk for drug addiction, which can be caused by a problem anywhere along the mesocorticolimibic system(9).
The various and profound negative effects that prolonged psychostimulant abuse has on the brain make it very difficult to distinguish between brain anomalies that might lead to drug use and brain dysfunction that is caused by drug use (9,22). Nevertheless, there are creative ways of studying brain circuitry that might predispose some to addiction. For example, ADHD and post-traumatic stress disorder (PTSD) are just two of many mental illnesses that are often exist simultaneously with drug addiction (9,22). Analyzing the neurological deviations associated with these disorders could provide clues about what activation patterns in the brain predispose certain people to addiction(22,23).
Both ADHD and PTSD can be considered disorders that predate addiction–ADHD because it is a developmental disorder and PTSD because it is caused by a traumatic event that often predates, and perhaps leads to, drug addiction (22). ADHD is characterized by attention deficits, impulsivity and lower performance on tests of inhibition (22). These characteristics of ADHD are attributed to diminished activation of the anterior cingulate cortex (ACC), which is part of the PFC associated with attention (22).
PTSD, on the other hand, is a disorder characterized by hypervigilance, emotional disturbance, and compromised response inhibition (22). These symptoms are associated with hyperactivation of the amygdala, which is the region of the lower brain associated with fear, anger, and threat perception (22). PTSD is also associated with overactivation of the cingulate cortex, a brain region that is recruited to process and regulate emotional stimuli and responses (22). The hyperactivation of the amygdala and the cingulate cortex can explain the hypervigilance that is characteristic of PTSD, as well as the exaggerated perception of threat (22). The brain with PTSD is not merely over-stimulated—there is also hypoactivation seen in the disorder (22). The medial prefrontal cortex (MPFC) and the ACC are two regions of the brain that are underactive in patients with PTSD (22). Both of these regions are active in higher-level executive control, and it is likely that the hypoactivity of these regions is responsible for the difficulties with response inhibition (22,23).
While the neurological components of ADHD and PTSD are quite different, it is important to bear in mind that breaking any part of a circuit can lead to the same end result—in this case, addiction (22). The different neurological abnormalities seen in each disorder lead to behavioral similarities that might be more important as indications of a person’s proclivity for developing an addiction (22). Some examples of behavioral defects seen in those with ADHD and PTSD include deficiencies in inhibitory control, information processing, executive function, working memory, and attention (22). All of these behavioral dysfunctions are also seen in drug addicts, regardless of comorbidity with any other mental illnesses, and it is easy to see how a person with dysfunctional inhibitory control would be more likely to fall into drug addiction; the inability to inhibit a desire to seek drugs is exactly the problem that leads to addiction (22,23).
Science has made some progress in addiction research. Modafinil is one drug that has had some success in treating addicts. It has cognitive enhancing effects, and it promotes wakefulness (12,22,23). Modafinil neurologically mimics cocaine, increasing circulating levels of DAA, and it establishes this concentration through its similar binding patterns to cocaine (12,22,23). Modafinil is different from cocaine in that it does not induce high levels of self-administration (1,22,23). In different trials with methamphetamine addicts, modafinil has improved verbal memory, attention and even enhanced PFC and ACC activation (22). These successes do not directly lead to addiction recovery, but they do give addicts the advantage of enhanced cognitive abilities (22). Addiction is a disorder associated with a weak PFC relative to the reward pathway, and modafinil can help those in treatment to strengthen their PFCs (22). In fact, there is a strong movement to use cognitive enhancement medication in order to counteract addiction, including methylphenidate, better known as Ritalin (22). Modafinil has been approved as treatment for narcolepsy and other sleep disorders and its approval as treatment for psychostimulant addiction might not be far in the future (22).
Many medical treatments succeed in spite of scientists’ ignorance of the way in which they work. Deep-brain stimulation (DBS) is just one such example. Placing electrodes in a specific part of the brain and then running a current through the electrodes has successfully treated depression and Parkinson’s, although it is unclear exactly how it functions. DBS has been successfully preformed in the nucleus accumbens of on one patient suffering from alcohol addiction, and the procedure did alleviate his addiction. The surgery was intended to treat a severe anxiety disorder and depression, and it was only because he had such debilitating comorbid disorders that the surgery was performed. There have not been DBS surgeries on humans with psychostimulant addictions; such invasive techniques are generally considered only as a last resort, and they are still in animal clinical trials.
It is easy to see how psychostimulants gained momentum so quickly in the 1900s, with endorsement from renowned figures like Freud, rampant publicity, and the desirable rush of energy, self-confidence, and euphoria that amphetamines and cocaine induce (1,5,11). While these drugs do have certain allure, it is important for the public to be aware of exactly how addictive they are, and just how little can be done to help those fighting with psychostimulant addiction. The days where amphetamines were called “mother’s little helper” are gone, and the medical community has replaced flippant prescriptions with a healthy skepticism towards such addictive drugs (11,28). Still, amphetamines are legally prescribed to many Americans, including children, and such remaining instances of psychostimulant prescription should be scrutinized (7).
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