Chapter 6 Stimulants
Stimulants • Stimulants are substances can enhance a person’s mental and physical state • Illicit stimulants: • Examples: cocaine and amphetamine • Licit stimulants: • Examples: caffeine and nicotine
Stimulants • For Discussion: • What is your daily stimulant use (Type and Amount) • Is your use about the physical and mental benefits of the stimulants for recreational purposes , or do you use them for some therapeutic effect?
Cocaine History Coca • Coca has been a staple dietary supplement and cornerstone to Ancient Andean culture (Inca 5000-2500 BC) throughout much of its history. Unprocessed coca leaves are commonly used in the Andean countries to make an herbal tea with mild stimulant effects similar to strong coffee, but is best known in most of the world for the stimulant drug cocaine that is chemically extracted from its new fresh leaf tips in a similar fashion to tea bush harvesting. However, the alkaloid content of coca leaves is low: between .25% and .77%, and production of cocaine from coca requires complex chemical processes.The Alkaloid concentration increases the extraction of cocaine. This means that chewing the leaves or drinking coca tea does not produce the high (euphoria) people experience with cocaine.
Cocaine History • Coca grows well in higher altitudes and is typically harvested from pruned plants (shrubs) • Coca was an important part of Inca culture • Used in religious ceremonies and as currency because chewing on the leaves increased strength, endurance, reduced fatigue, and could suppress appetite. • Some natives of the Andes still chew coca leaves to reduce fatigue and increase productivity ?
Cocaine History • Cocaine was in use in Europe by the 19th century Vin Mariani (Angelo Mariani’s Coca Wine) Used coca leaf extract in many other products including lozenges and tea
Cocaine History • Cocaine was also used in the United States in early versions of Coca-Cola and in many patent medicines
Cocaine History • Cocaine • was isolated from the plant before 1860 • processing 500 kilograms of coca leaves yields one kilogram of cocaine • By the 1880’s cocaine was undergoing medical experimentation and could be delivered by a hypodermic needle • It was discovered that cocaine could work as a local anesthesia. • Sigmund Freud - called cocaine the “magical drug” (see next slide)
Cocaine History • Early psychiatric uses: • Sigmund Freud studied use of cocaine as a treatment for depression and morphine dependence • Later opposed use of the drug after nursing a friend through cocaine psychosis (a form of Stimulant Psychosis, see next slide)
Stimulant and Cocaine Psychosis (sources linked) • Stimulant psychosisis a psychotic disorder that appears in some people who use stimulant drugs. Most commonly, stimulant psychosis occurs in drug abusers who take very large doses but, in rare cases, it can also present in patients taking therapeutic doses under medical supervision.The most common stimulants involved are amphetamines and cocaine. • Cocaine has a similar potential to induce temporary psychosis,with more than half of cocaine abusers reporting some psychotic symptoms at some point.Typical symptoms of sufferers include paranoid delusions that they are being followed and that their drug use is being watched, often with accompanying hallucinations, which supports the delusional beliefs.Delusional parasitosis with formication ("cocaine bugs") is also a fairly common reaction.Cocaine-induced psychosis shows sensitization toward the psychotic effects of the drug, meaning psychosis tends to become more severe with repeated, intermittent use.
Early Legal Controls on Cocaine • Between 1887 and 1914, 46 states passed laws to regulate the use and distribution of cocaine. • Cocaine had become widely used as a pleasure drug • Cocaine had become identified with despised and outcast groups of people including lower class whites, criminals, but especially with blacks • Press and politicians made unsubstantiated claims about cocaine use among southern blacks: • Falsely reported widespread used proportionately among blacks • Associated with increased violent crime • In 1900, the Journal of the American Medical Association published an editorial stating, "Negroes in the South are reported as being addicted to a new form of vice – that of 'cocaine sniffing' or the 'coke habit.'" Some newspapers later claimed cocaine use caused blacks to rape white women and was improving their pistol marksmanship.
Early Legal Controls on Cocaine • This fear (and negative press) lead congress to the passage of the Harrison Narcotics Tax Act, 1914. • 46 states passed laws to regulate cocaine between 1887 and 1914
Forms of cocaine • Coca paste • Cocaine paste, also known as coca paste, paco, or pasta base: a collective name given to several different cocaine products • Using simple precipitation methods and local ingredients — fresh-grown Andean coca leaf, kerosene, soda ash one is able to produce a chemically active “crude” cocaine in an easy and economic preparation in the same place as coca cultivation. In South America, this paste is often mixed with tobacco and smoked.
Forms of cocaine Cocaine hydrochloride • Conversion of cocaine paste into cocaine hydrochloride (salt) that cannot be heated to form vapors for inhalation even though it mixes easily into water • Cocaine is a weakly alkaline compound (an "alkaloid"), and can therefore combine with acidic compounds to form various salts. The hydrochloride (HCl) salt of cocaine is by far the most commonly encountered (most common form of pure cocaine) • Often insufflated by users, and may also be injected intravenously
Forms of cocaine Freebase vs. Crack Cocaine • Normal cocaine (Cocaine Hydrochloride) is the typical white powder people snort. This form is a water soluble salt of the cocaine free base and the HCl. This form also vaporizes at a temperature very close to the temperature at which it burns, making it difficult to smoke. • Crack cocaine is a cheap yet inefficient method of freeing the base cocaine molecule from the salt. It uses baking soda to remove the proton from the base. However, this safe, cheap method does not involve any purification steps, leaving some water and baking soda (impurity) along with the newly formed "crack" which forms crystals and floats to the top. So freebase cocaine along with other impurities are what make up crack cocaine. Crack or “rock: can be smoked • Freebase cocaine is formed by a similar process. However, ammonia is used to remove the proton and free the cocaine base. Diethyl ether (extremely flammable and volatile) is used to dissolve and remove the freebase cocaine. This can simply be siphoned off the top since ethyl ether does not mix with the water/ammonia solution. The Diethyl Ether evaporates and pure freebase cocaine is left behind.
Contemporary Legal Controls • Cocaine use increased in the late-1960s because amphetamines were harder to obtain • Prior to 1985, the major form of the drug available was cocaine hydrochloride • Most often insufflated, and was glamourized in the 1980’s • Usually sold in bulk amounts that were relatively expensive, and considered the champagne of recreational drugs • By 1985, Cocaine use was associated with status, wealth, and fame • By the mid-late 1980s, crack became available • Relatively inexpensive ($5 to $10 a hit) • Street level drugs were typically adulterated, and used to make profits • Smoked cocaine use was associated with poor, black Americans
Contemporary Legal Controls • Media and politicians focused on crack use among urban black Americans • Associated with violence and dependency (Remember 1914 ???) • Anti-Drug Abuse Acts of 1986 and 1988 (Ronald Reagan Presidency) • Penalties for sale of crack cocaine significantly more severe compared with powder cocaine • In 1988, the law was modified so that it applied to individuals convicted of simple possession of five grams of crack cocaine • By mid 1990’s congress directed the U.S. Sentencing Commission to study concerns about policy: • Penalties’ severity disproportionately impacted blacks (see Table 6.1, and next slide) • Exaggerated relative harmfulness of crack • Penalties too broad sweeping and targeted low level offenders
Cocaine Users - Discussion • Why do you think people are likely to use cocaine? • What do they think the benefits are? • What so you think are the risks? • 2) Why do you believe that blacks have been historically associated with cocaine abuse? • Does our society label users as “good” users and “bad users”? • Why?
Mechanism of Action • Cocaine’s mechanism of action is complex • Cocaine blocks reuptake of dopamine, serotonin, and norepinephrine, causing a prolonged effect of these neurotransmitters. • “By binding to the transporters that normally remove the excess of these neurotransmitters from the synaptic gap, cocaine prevents them from being reabsorbed by the neurons that released them and thus increases their concentration in the synapses (see animation). As a result, the natural effect of dopamine on the post-synaptic neurons is amplified. The group of neurons thus modified produces much more dependency (from dopamine), feelings of confidence (from serotonin), and energy (from norepinephrine) typically experienced by people who take cocaine.” (source)
Mechanism of Action • “In chronic cocaine consumers, the brain comes to rely on this exogenous drug to maintain the high degree of pleasure associated with the artificially elevated levels of some neurotransmitters in its reward circuits. The postsynaptic membrane can even adapt so much to these high dopamine levels that it actually manufactures new receptors. The resulting increased sensitivity produces depression and cravings if cocaine consumption ceases and dopamine levels return to normal.” (source) • It is possible the GABA and Glutamate also are affected by Cocaine
Cocaine Absorption • Chewing or sucking coca leaves • Slow absorption through the mucous membranes of the mouth • Results in slower onset and lower blood concentration of cocaine • Insufflation • “Snorting” cocaine hydrochloride • Absorbed through nasal mucous membranes • Rapid absorption and onset of effects, reaches the brain quickly • Intravenous injection • Very high concentration delivered to the brain • Rapid and brief effects, thus a favorite among compulsive users • Smoked • Smoking Crack is now preferred by most compulsive users • Route is less invasive and presents rapid and brief effects
Cocaine Elimination • Cocaine is extensively metabolized, primarily in the liver, with only about 1% excreted unchanged in the urine. • Cocaine is rapidly metabolized and removed from the system, with a half-life of about one hour. • The Major metabolites have a half-life of eight hours • These are detected by urine drug screens
Beneficial Uses • Local anesthesia: • Used medically since 1884 • Early applications were eye surgery and dentistry • Because of the abuse potential, synthetic replacements (procaine; aka. Novocain) have been developed. • Cocaine still remains in use for surgery in the nasal, laryngeal, and esophageal regions
Concerns: Acute Toxicity • No evidence that occasional use of small amounts is detrimental to health • Potential toxicity increases with larger doses • Acute cocaine poisoning leads to profound CNS stimulation which can lead to respiratory or cardiac arrest • Whether a drug produces a toxic effect, depends on the dose • Illicit cocaine is often adulterated and the adulterants may be more toxic than the drug • History of being cut with Levamisole • By April 2011, the DEA reported the adulterant was found in 82% of seizures • Levamisole suppresses the production of white blood cells, resulting in neutropenia and agranulocytosis. With the increasing use of levamisole as an adulterant, a number of these complications have been reported among cocaine users. Levamisole has also been linked to a risk of vasculitis. (source)
Concern: Chronic Toxicity • Binging • Drug is taken repeatedly and at increasingly high doses • Risks of binge use • Increasing irritability, restlessness, paranoia • Can result in paranoid psychosis – (see previous slide on Stimulant Psychosis) • Most seem to recover once the drug leaves the system
Concern: Chronic Cocaine Use source
Concerns: Dependence Potential • Cocaine dependence occurs in some users • Animal and human studies have shown that cocaine is a powerfully reinforcing drug • Example: Animals will readily self-administer the drug by lever-pressing • After binge use, some people experience withdrawal symptoms • Cocaine craving, irritability, anxiety, depressed mood, increased appetite, fatigue • However, these symptoms vary greatly among individuals, with some individuals exhibiting little or no symptoms.
Concerns: Reproductive Effects • “Crack Baby” phenomenon • Media reports overstated the expected long-term effects of cocaine exposure • Recent studies indicate no consistent associations between cocaine exposure and several developmental measures • Cocaine use during pregnancy • The use of cocaine during pregnancy carries more immediate risks, including and increased risk of miscarriage and torn placenta
Current Patterns of Use • National Survey on Drug Use and Health (NSDUH) and Monitoring The Future Study (MTF) surveys indicate: • Less than two percent of adults currently use cocaine (2010 data) • Down from a peak of 7 to 9 percent in the 1980s • In general, usage rates of cocaine and amphetamine tend to cycle in opposition to each other • When cocaine use decreases, amphetamine use may increase
Amphetamines History • Historically the Chinese used a medicinal tea made from “ma huang” (Ephedra) • Active ingredient is ephedrine • Stimulates the sympathetic branch of the autonomic nervous system (Sympathomimetic) • The stimulant and thermogenic effects of Ephedra sinica and other Ephedra species are due to the presence of the alkaloids ephedrine and pseudoephedrine. These compounds stimulate the brain, increase heart rate, constrict blood vessels (increasing blood pressure), and expand bronchial tubes (making breathing easier). Their thermogenic properties cause an increase in metabolism, evidenced by an increase in body heat. • (source)
Amphetamines History • Amphetamine • In the late 1920’s researchers synthesized and studied the effects of a new chemical that was similar in structure to ephedra • Amphetamine was patented in 1932 • Early medical uses: • Asthma (first used here for ephedrine replacement - bronchodilator) • Narcolepsy • Hyperactivity in children • Appetite suppressant • Stimulant
Amphetamines History • Wartime uses: • Increased efficiency and reduced fatigue among soldiers and pilots during WWII • 1960s “speed scene” • Many IV drug users used amphetamines either alone or in combination with heroin (speedball) – Speedball is so named because of the rush that occurs rapidly after injection, thus speeding up the “high” • Following this practice the street mane for cocaine became “Speed” • Most street amphetamines came from prescriptions because it was easy to get a prescription of amphetamines to treat depression or obesity (most desired on the street was methamphetamine) • Amphetamines became more tightly controlled (1970s), leading to: • Increased cocaine use • Increased illicit manufacture of methamphetamine
The Return of Methamphetamine • The Restriction of Amphetamines lead to the Illicit manufacture of methamphetamine • “Meth Labs” increases (Some names are "crystal meth", "meth", "speed", "crystal", "ice” and “crank”) • This manufacturing is dangerous and associated with toxic fumes and residue • The drug often contains impurities that may be toxic • Not as easy to create Meth as indicated on many internet videos • Methamphetamine abuse rose in the Western and Midwestern United States throughout the 1990s • Increases in Eastern U.S. cities were relatively modest • Cocaine remained the stimulant of choice
Amphetamine Pharmacology • Chemical structure of amphetamine is similar to the catecholamine neurotransmitters (see Figure 6.2, p. 139, text) • The methyl group in methamphetamines seems to make the molecule cross the blood brain barrier more readily, thus increasing CNS potency • Ephedrine is less able to cross the barrier • Thus, produces more peripheral and fewer central nervous system effects • Amphetamines are probably more potent releasers of norepinephrine which in turn mediates the euphoric effects of amphetamines. The amphetamine effects are probably the result of interactions with multiple neurotransmitters
Absorption and Elimination • Peak effects • 1.5 hours after oral ingestion • 5-20 minutes after intranasal administration • 5-10 minutes following intravenous injection or smoking • Half-life • 5-12 hours • Completely eliminated in approximately two days • Rapid tolerance (tachyphylaxis) can occur after high doses. • Tachyphylaxis is a medical term describing an acute (sudden) decrease in the response to a drug after its administration. This can sometimes be caused by depletion or marked reduction of the amount of neurotransmitter responsible for creating the drug's effect, or by the depletion of receptors available for the drug or neurotransmitter to bind to. This depletion is caused by the cell's reducing the number of receptors in response to their saturation (source)
Beneficial Uses • Depression • Treatment of choice during the 1950s–60s • Now used as an adjunctive therapy • Major advantage = antidepressant effects occur relatively rapidly • Weight control • In the 1960s, widely used to reduce food intake and body weight for short periods of time • Methamphetamine currently FDA-approved • Long-term effects on obesity unclear
Beneficial Uses • Narcolepsy • Uncontrolled daytime episodes of muscular weakness and falling asleep • Stimulants used to keep patients awake during the day • “Smart pills” • At a low level of arousal, may improve performance • At a high level of arousal, may decrease performance • Athletics • Under some circumstances, may produce slight improvements in athletic performance
Beneficial Uses • Treatment of Attention-Deficit Hyperactivity Disorder (ADHD) • Characterized by problems with inattention, hyperactivity, and impulsivity (see pg 142, DSM-IV-TR) • Stimulant medications can reverse catecholamine-associated deficits that may underlie ADHD • Concerns about abuse and side effects has lead to other treatment options • However, data suggest that stimulant is protective against substance abuse • Higher doses (non-therapeutic) doses do have abuse /dependence potential
Concerns: Acute Toxicity • Acute behavioral toxicity • Increases in feelings of power, suspicion, paranoia • In animals, very high doses may destroy catecholamine neurons • Caveat: dosing regimens used in animal studies do not mimic those used by humans • Contaminants formed during the illicit methamphetamine manufacture may be neurotoxic
Concerns: Chronic Toxicity • Paranoid psychosis following binge use • Possible reasons for psychosis include: • Heavy methamphetamine users may have schizoid personalities • Primarily due to sleep deprivation • No good evidence for permanent behavioral or personality disruption
Concerns: Dependence Potential • Can produce psychological dependence in some individuals • As defined by DSM criteria • A potent reinforcer in animals and humans • Abuse potential is likely dose-dependent • Small doses for medical use rarely lead to dependence
Concerns: Dependence Potential Data from The Lancet suggests amphetamine is ranked the 9thmost addictive and 6th most harmful of 20 popular recreational drugs.
Concerns: Dependence Potential End of presentation