PSYC 460 -- Notes on Drugs -- Dr. King Note: this is (with minor modifications) the text from the slides presented in class. The numbering corresponds to slide numbers in the presentation. 1) Drugs - Still chapter 4. 2) Drug Classification * There is no generally agreed-upon classification of psychoactive drugs. * So this one will have to do. 3) Dr. King's Drug Classification Scheme for Psychoactive Drugs * others (hard to classify) - nicotine, marijuana, PCP, etc. * stimulants - caffeine, amphetamines, methylphenidate, cocaine, etc. * depressants / sedatives / tranquilizers / anxiolytics - alcohol, barbiturates, benzodiazepines, etc. * opiates (narcotics) - opium, morphine, heroin, etc. * psychedelics / hallucinogens / psychotomimetics - LSD, mescaline, psilocybin, DMT, etc. * psychotherapeutics * antidepressants - MAOIs, tricyclics, SSRIs, SNRIs, etc. * antipsychotics - chlorpromazine, haloperidol, clozapine, etc. 4) A Quick Simpleminded Rundown of What They Do in the Brain * others (hard to classify) - various actions * stimulants - catecholamine agonists (mostly) * depressents, etc. - GABA agonists (mostly) * opiates (narcotics) - endorphin agonists * psychedelics, etc. - various actions on serotonin * psychotherapeutics * antidepressants - monoamine agonists (mostly) * antipsychotics - dopamine antagonists 5) Dependence Potential * Dependence has more to do with craving than with withdrawal avoidance. * Dependence potential often has to do with how the drug is taken and for what reasons. * Dependence means a user has lost control of his/her intake of the drug (denial aside!). 6) Dependence Potential * high to very high - heroin (IV), crack cocaine, morphine (injected), opium (smoked) 7) Dependence Potential * moderate to high/moderate - cocaine (snorted), tobacco (smoked), PCP (smoked), Valium, alcohol, amphetamines (oral) 8) Dependence Potential * low to low/moderate - caffeine, MDMA (ecstacy), marijuana, LSD, mescaline, psilocybin 9) What Are "Schedules" (A Legal Construct) * Schedule I - high abuse potential, no recognized medical use (in U.S.) * heroin, marijuana, MDMA * Schedule II - high abuse potential, currently accepted medical use * morphine, cocaine, methamphetamine * Schedule III - moderate abuse potential, currently recognized medical use * anabolic steroids, barbiturates, THC 10) Nicotine (Tobacco) * Tobacco smoking was discovered among the inhabitants of the "New World" by Columbus. * The first person to be observed smoking tobacco in Europe was imprisoned because it was believed he was possessed by the devil. * By the mid-1500s, "medical uses" had been found for tobacco, which legitimized its use. 11) Nicotine (cont.) * Nicotine was first isolated from tobacco in 1828 by two French chemists. 12) Nicotine (cont.) * Nicotine was finally recognized in the U.S. to have no medical use in the 1890s. * It has been used as an insecticide, however. * It is very toxic and very fast-acting. A cigar contains about two lethal doses. * low-level poisoning - dizziness, nausea * acute poisoning - tremors, convulsions, death (from paralysis of the respiratory muscles) * "Back in the lab," nicotine was the drug we least liked to handle. 13) Nicotine (cont.) * Nicotine occupies and activates the nicotinic acetylcholine receptor. However, it does not release from the receptor very quickly, so it has a short blockade effect. * Stimulates the release of adrenalin from the adrenal gland. * Shifts the cortical EEG to an activated pattern. 14) Nicotine (cont.) * Nicotine affects the appetite in two ways. * inhibits hunger pangs (stomach contractions) * deadens the taste buds * Nicotine withdrawal results in increased appetite, probably due to a return of taste sensitivity. (The old Freudian pearl that it has to do with deficient oral gratification is, to be polite, rubbish!) 15) Nicotine (concluded) * Tolerance develops rapidly, probably due to induction of liver enzymes that break it down. * Nicotine is highly addictive. This is probably because it activates the mesolimbic dopamine pathway that terminates in the nucleus accumbens in the basal ganglia. 16) Caffeine * Caffeine and its relatives, theophylline and theobromine, are chemically known as xanthines. * It is the most commonly used psychoactive substance in existence. * 80% of Americans use it on a daily basis. 17) Caffeine (cont.) * Most modern kitchens have a device specially designed for the extraction of caffeine from plant material. It's called a coffee maker. * Other sources of caffeine: tea, colas, chocolate, cocoa, "energy" drinks (which contain less caffeine than a cup of coffee!), OTC "pep" pills and diet pills. * Aside: caffeine that is removed from decaf coffee is often added to colas. 18) Caffeine (cont.) - chart of caffeine content of various substances 19) Caffeine (cont.) * Caffeine was first isolated from coffee in 1820. * Caffeine is taken up fairly rapidly, reaches its maximal pharmacological effect in the CNS in about 2 hours, and has a half life of about 3 hours in the human body. * Tolerance develops rapidly and is long-lasting. * Both psychological and physical dependence occur. The most reliable withdrawal symptoms are headache (within 24 hrs.), fatigue, and lassitude. Withdrawal takes about a week. 20) Caffeine (cont.) * At one time it was believed that the action of caffeine was on the second messenger system at catecholamine neurons. * Today we think the primary action is blockade of adenosine receptors. * adenosine - promotes sleep and suppresses arousal; builds up in the brain during wakefulness * Causes cortical arousal and activation of the EEG. 21) Caffeine (concluded) * behavioral/psychological effects * stimulation, arousal, elevation of mood * relief from fatigue * relief of headache (withdrawal can produce headaches and lead to the onset of migraines) * precipitation of panic attacks in people prone to them (at a dose equivalent to about 5 cups of coffee) * there is no evidence that caffeine (or coffee) will help you "sober up" 22) Amphetamines * All amphetamines are variants of this structure (alpha-methylphenylethylamine diagram) * Adding methyl groups to it makes it more easily cross the blood-brain barrier. * Adding hydroxyl groups to it makes it less easily cross the BBB. 23) Amphetamine (cont.) * Ephedrine is an amphetamine (beta-hydroxy-methamphetamine). * Methamphetamine is an amphetamine. * Methylphenidate (Ritalin) is NOT an amphetamine (athough it is commonly called one and has similar effects). 24) Amphetamine (cont.) * Amphetamines were first known by the Chinese and were used in herbal form. We call the herb Ephedra. * Ephedrine, the active compound in Ephedra, has largely "sympathomimetic" effects. * nasal and bronchial dilation * elevated blood pressure * Knowledge of ephedrine led to the synthesis and investigation of similar compounds. 25) Amphetamine (cont.) * Amphetamine was first synthesized in the 1920s and patented in 1932 as Benzedrine. * It was first used in the treatment of asthma, and later in the treatment of narcolepsy. * It also became used as an appetite suppressant and to treat hyperactivity in children. * "Bennies" became a favorite of long haul truckers to help keep them awake and of college students who had to cram for exams. 26) Amphetamines (cont.) * In the 1950s and 1960s it became widely and easily available as a prescription treatment for depression and obesity. * In the 1960s, amphetamines became among the most popular drugs of abuse and became known as "speed" (a name previously applied to cocaine), especially when used IV. * In 1965 amphetamines were labelled dangerous by the Federal government and became restricted. In the public's mind, use of the drug became associated with "drug-abusing hippies." 27) Amphetamines (cont.) * There were three consequences. * The "hippies" began to lose interest in this synthetic drug and took up use of a "more natural" plant-derived stimulant - cocaine. * By 1980 if you were buying "speed" on the street, you were surely getting a look-alike pill containing caffeine, ephedrine, and other legal substances. * Illegal meth labs became much more common. 28) Amphetamines (cont.) * The chemical structure is very similar to that of the cathecholamine neurotransmitters. * Apparently, amphetamines are "mistaken" for catecholamines in the brain. * d-Amphetamine (Dexedrine) is several times more potent in the CNS than l-amphetamine. (Benzedrine is a 50:50 mix.) * Amphetamines stimulate release of all the monoamine neurotransmitters. 29) Amphetamines (cont.) * The euphoria ("rush") associated with amphetamine use is commonly attributed to its ability to release dopamine in the nucleus accumbens (mesolimbic DA pathway). * However, specific DA antagonists do not block this effect of amphetamine. * High doses are so good at dumping monoamine neurotransmitters that depletion can occur, leading to a "crash." 30) Amphetamines (concluded) * problems * impaired decision making * possible increase in violent behavior (??) * amphetamine psychosis * compulsive, stereotyped behavior * neurotoxicity after high doses * craving, lethargy, and depression upon withdrawal 31) Do Stimulants Cause Brain Damage? 32) Cocaine * Cocaine is derived from the leaves of Erythroxylon coca, the cocoa plant. * This plant has been cultivated by South American Indians for 7000 years. 33) Cocaine (cont.) * It was introduced to Europeans as coca wine in the late 19th century. 34) Cocaine (cont.) * ...and to Americans as Coca Cola. * The name was derived from the source of the two stimulants it contained: cocoa leaves and cola beans. 35) Cocaine (cont.) * It's first medical use was as a local anesthetic. (Cocaine Toothache Drops - 15 cents) * It was replaced eventually by procaine (Novocain). 36) Cocaine (cont.) * It was also used in the treatment of depression and morphine dependency. * These uses were endorsed by Sigmund Freud. 37) Cocaine (cont.) * Like nicotine, it's chemical structure is not very revealing of what it might do in the brain. 38) Cocaine (cont.) * two forms * cocaine hydrochloride * so stable it does not form vapors when heated - so can't be smoked * dissolves in water, so can be snorted * cocaine freebase (crack) - forms vapors when heated 39) Cocaine (cont.) * Cocaine is broken down in the liver. It has about a 1-hour half life. * Cocaine is a powerful stimulant (a very effective DA reuptake blocker). * arousal/activation * relieves fatigue * reduces appetite 40) Cocaine (cont.) * acute cocaine poisoning - from high doses * convulsions * respiratory arrest * cardiac arrest * cocaine psychosis - similar to amphetamine psychosis * Lab animals allowed to self-administer cocaine will do so until they die. 41) Cocaine (concluded) * Physical withdrawal may not occur. * Craving, irritability, and depression are common upon withdrawal. * The "crack baby" phenomenon was mostly media hype. 42) Barbiturates * Barbiturates are sedative drugs based on the barbituric acid molecule. * They have some of the most colorful street names: reds, red birds, red devils, blues, blue heavens, yellows, yellow jackets, tooties, and goofballs. 43) Barbiturates (cont.) * "downers" * sedatives - tranquilizers or anxiolytics * hypnotics - sleeping pills * as opposed to "uppers" - stimulants * Similar depressant effects are produced by alcohol and inhalants. * Once among the most frequently prescribed drugs, today they have largely been replaced by the benzodiazepines (Valium, etc.). 44) Barbiturates (cont.) * Barbiturates were introduced into clinical use in 1903. (Marketed by Bayer as a hypnotic and anesthetic. They were also used as anticonvulsants.) * They are classified as "short-acting" (15-min. onset, 2-3 hrs. duration), "intermediate-acting", and "long-acting" (1 hr. onset, 6-10 hrs. duration). * There are ultra-short acting barbiturates that will put you to sleep within a minute of IV injection. 45) Barbiturates (cont.) * Tolerance develops rapidly due to induction of liver enzymes. * They depress respiration and in high doses or in combination with alcohol can cause respiratory arrest. * In the 1950s and 1960s, they were the drugs of choice for committing suicide. An "overdose of sleeping pills" meant suicide by barbiturate. * Today they are used to euthanize animals, in physician assisted suicide, and in capital punishment by lethal injection. * Sodium Pentothal, or "truth serum," is also a barbiturate. (It doesn't really make you tell the truth!) 46) Barbiturates (cont.) * Barbiturates do cross the placental barrier, so women taking them while pregnant can give birth to barbiturate-addicted babies. * withdrawal - characterized by the opposite effects of the drug itself * dysphoria * anxiety, hyperventilation, panic attacks * insomnia * seizures 47) Barbiturates (concluded) * Barbiturates act at a barbiturate binding site on the GABA-A receptor, where they cause the chloride channel to remain open longer. * The endogenous ligand is unknown. * They may also have a secondary action of blocking AMPA receptors. 48) Some Other Sedatives * "Mickey Finn" or knock-out drops - chloral hydrate (takes effect in about 30 min.; puts you to sleep in about an hour) * Methaqualone - sold under trade names Quaalude and Sopor * benzodiazepines - Librium, Valium, Xanax, Ativan, Halcion, and about 50 others * Rohypnol ("roofies") - a benzodiazepine (now changes color when added to alcohol) * GHB - gamma-hydroxybutyrate (a GABA-like chemical) * Ambien/Lunesta/Sonata - have a benzodiazepine-like action at the GABA-A receptor 49) Answers to Questions * euthanizing a pet (small animals) * may be done in one or two injections * sodium pentobarbital (Nembutal) is used * tranquilizer guns - typically not barbiturates (why not?) * opiates - fentanyl, etc. * heavy duty antipsychotics like haloperidol * ultra-short-acting benzodiazepines * paralytics like curare * "cocktails" of the above * death penalty by lethal injection - a three-stage process * sodium thiopental - an ultra-short-acting barbiturate * pancuronium - a paralytic that stops breathing (curare-like) * potassium chloride - stops the heart 50) Morphine and Heroin * These drugs are either derived from the opium poppy (Papaver somniferum) or are synthetic work-alikes. * Opium has been known and used medically for at least 6000 years. 51) M & H (cont.) * Morphine was first isolated from opium in 1806, and is the primary active ingredient in opium. (Codeine was isolated in 1832.) * The first widespread use of morphine was in the American Civil War for relief from pain and treatment of dysentery. * Morphine addiction was for a time called "the soldiers' disease." * Heroin (diacetylmorphine) was first marketed by Bayer in 1898 (as a non-habit-forming replacement for codeine). 52) M & H (cont.) * Heroin enters the brain faster than morphine. Why? (~3X as potent) * Once in the brain, heroin is converted to morphine. So for all intents and purposes, they are the same drug. 53) M & H (cont.) * patent medicines - coughs, asthma, teething pain, "fretfulness" 54) M & H (cont.) * In the 1880s the typical users of opium in this country were middle-aged housewives who may have ordered their opium from the Sears catalog. 55) M & H (cont.) * today there is a large number of synthetic opiates. They all work the same way. (Endorphin agonists.) * meperidine (Demerol) * oxycodone (Percodan, Oxycontin) * hydrocodone (Vicodin) * propoxyphene (Darvon) * fentanyl (Sublimaze) 56) M & H (cont.) * For decades everybody believed there was an opiate receptor in the brain. * It was discovered in the 1970s. * Then we had to ask, "Why the heck is that there?" * The endogenous ligands were discovered in 1974. 57) M & H (cont.) * leu-enkephalin, met-enkephalin * endorphins * dynorphins * They all act at one or another type of opioid receptor in the brain. * Endorphins are released from the pituitary gland in response to stress. * Enkephalins are released from the adrenal gland. 58) M & H (cont.) * As pain relievers, these drugs seem to work primarily on the emotional component of pain (suffering), and only secondarily on the sensation of pain. * They are also used for the treatment of intestinal disorders, diarrhea, and as cough suppressants. * They are abused because of their potential to create euphoria. * There is NO credible evidence that naturally occurring opioids produce euphoria. 59) M & H (cont.) * Tolerance develops to most if not all the effects of opiates, requiring the dose to be increased if used repeatedly. * Cross-tolerance occurs between all opiates. * Behavioral tolerance - the effect of opiates used repeatedly is less if they are used in a familiar setting. (This can lead to overdosing in unfamiliar settings.) 60) M & H (cont.) * After chronic use of high doses, a characteristic abstinence syndrome occurs when the drug is withheld. * 6 hrs: craving, anxiety * 12 hrs: yawning, sweating, runny nose, teary eyes * 18 hrs: goose bumps, tremors, hot and cold flashes, aching bones and muscles, loss of appetite * 24 hrs: increased BP, increased body temperature, increased respiratory rate and depth, nausea * 36-48 hrs: vomiting, diarrhea, seizures in those prone to them 61) M & H (concluded) * acute toxicity (overdose) * respiratory depression - due to the respiratory centers of the medulla becoming less sensitive to carbon dioxide in the blood; this is very much accentuated by alcohol and other sedatives, and most deaths are due to the combination * pinpoint pupils * coma * treated with naloxone - an endorphin receptor blocker 62) Hallucinogens: An Overview * indole hallucinogens - LSD, lysergic acid amide, DMT, 5-methoxy-DMT, psilocybin * catechol hallucinogens - mescaline (peyote), DOM (STP), MDA, MDMA (ecstacy) [last 3 are amphetamine derivatives] * delirants * PCP, ketamine, dextromethorphan, nitrous oxide * anticholinergics - belladonna (atropine, scopolamine), mandrake, henbane, datura * amanita muscaria (ibotenic acid, muscimol) * salvia divinorum 63) LSD * myths * People on LSD have gone blind from staring into the sun. (False.) * LSD causes chromosomal damage. (True, but no more so than any other drug.) * The Beatles song Lucy in the Sky with Diamonds was written about LSD. 64) LSD * truths * LSD is one of the most potent psychoactive substances known. (True. It becomes active at a dose of about 50 micrograms, or less in some people, about 1/1000 the dose required for most drugs.) * If you buy mescaline (or other exotic hallucinogens) on the street, you are almost certainly getting LSD. * LSD is about the most incredibly boring drug to study in rats that you can possibly imagine! 65) LSD (cont.) * LSD is one of the least toxic drugs known. * TI = 400 (in rats) * no known physical dependence 66) LSD (cont.) * Only a very small amount of ingested LSD gets to the brain. * Half life is about 3 hrs. * Tolerance develops rapidly after only a few daily doses (and is virtually complete). * Cross-tolerance occurs with psilocybin and mescaline. * Effects are blocked by chlorpromazine (Thorazine) and certain other antipsychotics. 67) LSD (cont.) * LSD acts at a variety of serotonin receptor subtypes, but it is agonistic at some and antagonistic at others. * The most specific action of LSD (as well as psilocybin and mescaline) is at the 5-HT(2A) receptor, where it is a direct receptor stimulator. * (Not all effects are blocked by serotonin receptor blockers, however.) 68) LSD (cont.) * the 5-HT(2A) receptor * Hallucinogenic effects are highly correlated with a drug's affinity for this receptor. * Activation of this receptor is necessary for hallucinogenic effects. 69) LSD (cont.) * the 5-HT(2A) receptor (cont.) * metabotropic with a complex mechanism * located throughout the CNS (and body) but esp. in the neocortex * enhances glutamate release * interacts with other neurotransmitter receptors 70) LSD (cont.) * It's now thought that the effects of these classic hallucinogens are mediated by 5-HT(2A) receptors on the apical dendrites of pyramidal cells in layer 5 of the prefrontal cortex. 71) LSD (concluded) * Unfortunately, that is where the story seems to end at the present time. * Prefrontal cortex function is poorly understood except in the most general terms. It has an "executive function" and is important in "cognitive functioning." * Schizophrenia, bipolar disorder, and ADHD may be related to malfunctions in prefrontal cortex. * Clozapine and some other antipsychotic drugs block these receptors.