PSYCHOSTIMULANTS: COCAINE AND AMPHETAMINES Classification of some CNS stimulants Class Mechanism of action Examples Behavioral stimulants Augmentation of Cocaine norepinephrine and dopamine Amphetamines Methylphenidate (Ritalin Pemoline (Cylert) Phenmetrazine (Preludin) Clinical antidepressants Blockade of norepinephrine Imipramine (Tofranil) reuptake Amitriptyline (Elavil) Increased norepinephrine, Tranylcypromine (Parnate) secondary to MAO inhibition Blockade of serotonin reuptake Fluoxetine (Prozac) Legal recreational drugs Blockade of adenosine receptors Caffeine Stimulation of acetylcholine Nicotine receptors • Psychostimulant Effects: elevated mood, euphoria, and alertness, reduced fatigue, increased energy, decreased appetite, improved task performance, relief of boredom, increased motor activity. • Examples of psychostimulants: 1. cocaine 2. amphetamines (dextroamphetamine and methamphetamine) 3. amphetamine derivatives used to treat ADHD (methylphenidate; pemoline; Cylert) 4. variety of drugs formerly used to treat obesity (fenfluramine; Pondimin, phentermine; under trade names as lonamin, Obe-Nix, Adipex-P, Oby-Trim, and Fastin, and phenmetrazine; Preludin) 5. caffeine and theophylline (psychoactive drug in coffee and other caffeinated beverages) and nicotine (ingredient in tobacco). • All stimulants subject to compulsive abuse, and have limited therapeutic use, significant side effects and toxicity. • Common side effects (cocaine and amphetamines): anxiety, insomnia, and irritability • High doses: intense irritability and anxiety and psychotic behaviors • Low doses: alerting, arousing response not unlike normal reaction to an emergency or to stress (e.g. increase blood pressure and heart rate, pupils dilate, skin to internal organ blood flow shifts, and rise in blood oxygen and glucose levels) Cocaine - Historical Facts • Erythroxylon coca leaves (Peru and Bolivia) • Social use: religious, mystical, stimulant, and medicinal purposes-to increase endurance, promote sense of well-being, and alleviate hunger (usual total daily dose ~ 200 mgs) • 1859: active alkaloid in coca isolated and named cocaine. • 1884: Freud advocated use of cocaine to treat depression and alleviate chronic fatigue. He described cocaine as a “magical drug" and even wrote a "Song of Praise" to it. • 1884: Koller demonstrated cocaine's local anesthetic properties and for ophthalmologic surgery. • 1885: cocaine incorporated (along with caffeine) in popular patent medicine later known as beverage Coca-Cola, until 1903 (~60 mgs/8 ounce serving) • 1891: at least 200 reports of cocaine intoxication and 13 deaths reported. • 1914: Harrison Narcotic Act banned cocaine in medicines and beverages. • 1924: American Medical Association reviewed 43 deaths of patients who had been under local cocaine anesthesia and attributed 26 of those deaths to cocaine toxicity. • 1920s: Use of cocaine rose then decreased during 1930s, when amphetamines became available, presumably because cost less and produced longer-lasting effects. • 1960s: cocaine not used much until federal restrictions on amphetamine distribution raised cost of amphetamines, making cocaine attractive once again. • Net effects indistinguishable as euphoriants …availability, price, and sociocultural considerations now largely determine comparative popularity of the two. • 1970s: cocaine again became popular; in mid-1980s, smoking of concentrated preparations of cocaine (free base and crack cocaine) opened new era in cocaine abuse characterized by high- dose, rapid-onset effects with rapid development of dependence. • 20-30 million in U.S. have used cocaine; ~ 4 million people use it regularly, and ~ 2 million are "hard core" cocaine users. • At peak use, ~ 800,000 Americans had cocaine daily; today a number closer to 300,000 is likely (result of intensive antidrug campaign?)...number of users has not decreased. • Cocaine addicts: typically young (12 to 39 yrs), poly drug-dependent, and male (75%); tend to have coexisting psychopathology (30% anxiety disorders, 67% clinical depression, and 25% paranoia); 85-90% are alcohol dependent. • Associated with violent premature deaths, including homicides, suicides, and accidents. Cocaine Chemistry • Extracted as coca paste (60-80% cocaine), each leaf contains 0.5-1.0% C. • Coca paste converted to hydrochloride salt before exportation and sold as cocaine hydrochloride ("crystal" or "snow"). • Inhaled, cocaine hydrochloride provides ~10-25 mgs into each nostril; • Hydrochloride salt form not suitable for smoking, because it decomposes at temperatures required to vaporize it....thus • Hydrochloride form altered to base form, by extraction in ether ("free base") • Cocaine base or "crack," from cracking sound it makes when heated • Absorbed from: mucous membranes, gastrointestinal tract, and lungs. • Detoxified in plasma and liver...only small amounts excreted unchanged Cocaine Absorption • Routes: oral (chewing), intranasal (snorting), intravenous (mainlining), and inhalation (smoking or free-basing). • Orally: absorption over ~I hour, with ~75% metabolized in liver on first pass...thus, only ~25% reaches brain, eliminating feeling of "rush" that follows other routes. • Intranasally: poorly absorbed, as hydrochloride salt poorly crosses mucosal membranes....vasoconstriction limits absorption....20-30% absorbed, with peak levels in 30-60 min. • Inhalation: (smoked base), particles trapped in nose while others pass into trachea and lung, from which absorption is rapid and complete…onset of effects: seconds, and persist for 5-10 minutes…~6-32% of initial amount reaches plasma, remainder undergoes pyrolysis before inhalation. • Intravenous injection bypasses all barriers to absorption, placing drug immediately into the bloodstream....30-60 second delay in onset of action Cocaine Distribution and Elimination • Into brain rapidly; brain concentrations far exceed plasma concentrations • After brain penetration, cocaine redistributed to other tissues. • Freely crosses placental barrier, achieving levels in unborn equal to mother. • Half-life of 30-90 min, and almost completely metabolized by liver enzymes • Major metabolite is inactive benzoylecgonine, detected in urine for ~3 days, and much longer (15-22 days) in chronic users. Small amounts metabolized to an active intermediate (norcocaine). • Urinary detection of benzoylecgonine forms basis of drug testing • Persistence of metabolite in urine implies long-term users accumulate drug in body tissues, from which it is later absorbed into plasma, metabolized, and excreted...cocaine metabolites toxic to liver Cocaine Pharmacodynamics • Three prominent actions: local anesthetic, blood vessels constrictor, and psychostimulant with strong reinforcing qualities…compulsive drug abuse. • Potentiates synaptic actions of dopamine, norepinephrine, and serotonin via ability to block transmitter reuptake into presynaptic terminals • Dopaminergic action crucial to behavior-reinforcing and psychostimulant properties...both dopamine and cocaine decrease discharge rate of ventral tegmental area and nucleus accumbens neurons. • Dopamine exerts inhibitory effects on post-synaptic receptors; mechanistically cocaine potentiates dopamine postsynaptic-induced decrease in firing rate. • Cocaine binding to transporter induces a change in dopamine-binding site that decreases affinity of dopamine. • Two of five (D1 and D2) dopamine receptors involved in cocaine action. • D2 receptors underlie positive effects on behavior, reinforcing and locomotor effects, and stereotypical behavioral effects. • Serotonin depletion increases efficacy of cocaine as a positive reinforcer, thus cocaine actions on serotonin contribute aversive effect limiting its self-administration. • Serotonin uptake inhibitor fluoxetine enhances discriminative stimulus effects of cocaine. • Chronic exposure of postsynaptic receptors to high dopamine levels leads to decrease in postsynaptic dopamine receptors (down-regulation; subsensitivity) and increase dopamine transporter. Cocaine Side Effects of Short-Term, Low-Dose Use • Non-toxic physiological responses: increases in: alertness, motor hyperactivity, tachycardia, vasoconstriction, hypertension, bronchodilatation, body temperature, pupillary dilatation, glucose availability, and blood flow. • Enjoyable psychological effects: low doses of cocaine (25-150 mgs) depending on tolerance and route of administration. • Major psychological changes: mood (giddiness, enhanced self-consciousness, and boastfulness), cognition, drive states (hunger, sex, thirst)... talkative, garrulous, with tangential incoherent speech. • Mild euphoria with anxiety (~60-90min), then protracted anxious state (hrs). • Major physiological and behavioural changes: suppressed appetite with later rebound, delayed sleep, increased motor activity, and restlessness • After "high", anxiety, depression, and paranoia follow...rapid shift causes user to crave more drug. • Drug craving becomes intense and forms a part of withdrawal syndrome. • Higher doses: loss of coordination, tremors and eventually seizures, followed by depression, dysphoria, anxiety, somnolence, and drug craving. • Medical complications: snorted - chronic rhinitis, nasal septum perforations, and loss of sense of smell...intravenous - diseases transmitted by needle (hepatitis and AIDS) and infectious endocarditis (infections of heart valves)...smoking crack - pulmonary difficulties and black sputum. Cocaine Side Effects of Long-Term, High-Dose Use • Toxic symptoms: anxiety, sleep deprivation, hyper-vigilance, suspiciousness, paranoia (toxic paranoid psychosis). • Other high-dose, long-term effects: sexual dysfunction, interpersonal conflicts, severe depressive conditions, dysphoria, and bizarre and violent psychotic disorders that last days or weeks after quitting • Acute toxic dose: ~1-2 mgs/kg...thus, 70-150mgs of cocaine is a toxic, one-time dose for a 150- pound person...physiological toxicity follows higher doses. • Cardiovascular and neurovascular sequelae: strokes in healthy, young individuals, persistent alterations in blood perfusion of brain, heart oxygen deprivation, cardiac arrhythmias, and seizures. • Chronic cocaine-induced psychiatric syndrome: affective disorders, schizophrenia syndromes, personality disorders, etc. • Cocaine addicts personality profiles: reckless, rebellious, and low tolerance for frustration and craving for excitement. • Cocaine addicts typically abuse opiates and alcohol either to enhance effects of cocaine or to medicate themselves for unwanted side effects: calming jitters, dulling perceptions, and reducing paranoia. • Intravenous drug users often take cocaine and heroin together in mixture “speedball”. Cocaine Fetal Effects • Fetal cocaine syndrome (jittery baby syndrome) and infants known as "crack babies." • Not well defined, since most fetal effects related to vasoconstriction, hypertension, and infarcts at any time during gestation and in any structure. • To determine possible effects on fetus, must examine not only indirect maternal effects on fetal development but also direct teratogenic effects. • Indirect effects on fetus result from vasoconstrictive action in mother, which decreases blood flow to uterus and reduces fetal oxygenation. • Results of fetal hypoxia: placental detachment, placental insufficiency, preterm or precipitous labour, fetal death (stillbirths), and low birth weight...and can lead to intrauterine growth retardation, small head size (microcephaly), and aberrations in brain development. • Unborn is exposed to cocaine even before fertilization, because cocaine can bind to sperm. • Cocaine promotes destructive lesions, leading to Neonatal Neurological Syndrome typified by: abnormal sleep patterns, tremors, poor feeding, irritability, seizures, and increased risk/incidence of sudden infant death syndrome (SIDS). • 50,000-100,000 babies born each year to mothers who have used cocaine during pregnancy • Crack babies show difficulty with unstructured play and low tolerance for frustration; also structure input and information poorly...and show high incidence of ADHD. Treatment Problems of Cocaine Abuse • Variety of psychological, behavioral, and pharmacological approaches tried with major complications to overcome: 1. Intensity of both drug effect and behavior-reinforcing action of cocaine. 2. Pronounced tendency toward relapse, with cocaine acting as cue to increase craving for drug. 3. Virtually all cocaine addicts have additional drug dependencies and/or psychiatric disorders, including affective disorders, bipolar disorder, borderline personality disorder, antisocial personality disorder, and eating disorders. • Given these complications, needs of cocaine addict are at least 5-fold: 1. immediate abstinence 2. diagnosis of any coexisting disorders 3. determination if addiction is primary disorder or secondary to other disorders 4. maintenance of abstinence long enough to diagnose and begin treatment of coexisting disorders 5. prevention of relapse Treatment Approaches of Cocaine Abuse • Treatment approaches are many, from classical "12-step" recovery programs (AA) to psychopharmacotherapy, psychotherapy, or cognitive-behavioral approaches. • Abstinence essential and must be monitored by frequent, unannounced urine tests to screen for drugs. • 3-phase cocaine abstinence model: phases called crash, withdrawal, and extinction • Crash (9 hrs-4 days); user is uninterested in using cocaine, appearing quite depressed and somnolent. • Withdrawal (1-10 wks); max relapse potential/drug craving. • Extinction continued monitoring required since conditioned cues can trigger craving and result in relapse. • Psychopharmacotherapy to treat cocaine abuse: 1. antagonize the effects of cocaine at its receptors 2. produce an aversive (Antabuse-like) reaction 3. treat the coexisting psychiatric disorder 4. reduce cocaine craving and withdrawal • To date, no successful antagonists are available, nor are any aversive drugs; thus, psychopharmacotherapy aimed at utilizing drugs to attenuate drug craving. • Most popular drug for reducing craving is antidepressant desipramine. • Desipiramine relieves craving and withdrawal; effect is not predictable; positive effects short-lived • Other agents include: antiparkinsonian dopamine receptor agonist bromocriptine, the amino acid tyrosine, phenothiazines, (antipsychotics-antidopaminergics), other antidepressants, the mood stabilizer lithium, and the anticonvulsant carbamazepine. AMPHETAMINES AND RELATED DRUGS Amphetamine - Historical Facts • Amphetamines: methyl derivative methamphetamine, and several other derivatives (methylphenidate, fenfluramine, pemoline) exert stimulant effects resembling cocaine. • 1888: synthesized, but not used for medicinal purposes until 1930s, when found to increase blood pressure and stimulate CNS, and cause bronchodilatation. • 1935: treat narcolepsy; thought not to pose threat to health • 1935-1946: list of 39 conditions for which drug could be used: schizophrenia, morphine addiction, tobacco smoking, heart block, head injury, radiation sickness, hypotension, seasickness, severe hiccups, and caffeine dependence. • World War II: to fight fatigue and enhance battle performance • 1940s: large-scale abuse (usually oral ingestion) and continued to be used (and abused) as diet aid. • 1960s: abuse pattern changed with advent of injectable forms. Amphetamine Mechanism of Action • Indirect-acting catecholamine agonists: CNS effects exerted by causing release of newly synthesized catecholamines (especially dopamine) from nerve terminals. • Behavioral stimulation and increased psychomotor activity due to stimulation of dopamine receptors in mesolimbic system (including nucleus accumbens). • High-dose stereotypical behavior (constant repetition of meaningless acts) involves dopamine neurons in caudate nucleus and putamen of basal ganglia. • Increase in aggressive behavior complex...seen primarily in adults; in children they reduce aggressive behavior and activities characteristic of ADHD. • Potent anorectics: decrease appetite but tolerance to satiating effects develop rapidly; Involves lateral hypothalamus but may also involve serotonin neurons, which, when activated, produce satiety. Amphetamine Pharmacology • Psychomotor stimulant in the CNS: increased alertness, euphoria, excitement, wakefulness, reduced fatigue, loss of appetite, mood elevation, increased motor and speech activity, and improved task performance, dexterity loss. • Excreted in urine and detectable up to 48 hrs after use. • Low oral doses: (2.5-20 mgs) increase in blood pressure, with reflex slowing of heart rate, relaxation of bronchial muscle • Moderate doses (20-50 mgs): stimulation of respiration, slight tremors, restlessness, a greater increase in motor activity, insomnia, agitation, appetite suppression, wakefulness, and causes sleep deprivation (recovery takes many weeks). • High dose (>50 mgs): stereotypical behaviors (continual, purposeless, repetitive acts), aggression and violence, paranoid delusions, severe anorexia, and state of amphetamine psychosis, indistinguishable from acute schizophrenia attack. • Chronic amphetamine in animals, associated with: persistent depletion of both dopamine and enzyme tyrosine hvdroxylase (synthesis of dopamine)...thus, toxic to dopamine-releasing neurons. • Loss of responsiveness to "natural reinforcers" develops… dopamine neurons lose their sensitivity to dopamine. • Other harmful high-dose effects: psychosis and abnormal mental conditions, weight loss, skin sores, infections resulting from neglected health care, poor eating habits, and lack of sleep...including deterioration in social and occupational affairs. • Toxic doses vary widely...severe reactions can occur from low doses (20-30 mgs) whereas persons who do not have tolerance have survived doses of 400-500 mgs. Amphetamine Dependence and Tolerance • Prone to compulsive abuse (induces psychological dependence). • Dependence follows classical positive conditioning model; positive reward leads to further use. • Tolerance rapidly develops and accompanied by dysphoria, sedation, lassitude, and drug craving...solution to this state is taking more drug in higher and higher doses, which starts a vicious cycle of drug use and withdrawal. • At this point, tolerance to euphoriant effects develop, and periods of "binging" begin. • Tolerance leads to further drug intake, social withdrawal, and a focus on procuring drugs. Amphetamine Therapeutic Uses and Status • Medical uses are restricted and often controversial and include treatment of: 1. narcolepsy (application is now rare.) 2. attention deficit hyperactivity disorder 3. obesity • Note: amphetamines are not of much value in treating major depression (because of great potential for addiction and general lack of therapeutic efficacy). Amphetamines and Attention Deficit Hyperactivity Disorder • Since 1936 started with amphetamine and has progressed to use of methylphenidate (Ritalin), pemoline (Cylert), and, more recently, the antidepressant nortriptyline. • Evolution of terminology for the disorder: "minimal brain dysfunction" to "minimal brain disorder" to "hyperactivity syndrome" to "attention deficit disorder" to present ADHD. • No definitive CNS pathology has been demonstrated, however a dopamine hypothesis of ADHD, has evolved invoking a disorder of polysynaptic dopaminergic circuits, between prefrontal and striate centers. • Affects 6% of school-age children, characterized by: inattentiveness, impulsivity, and hyperactivity that are persistent and severe to cause functional impairment at school, home, and with peers....evidence that disorder may be inherited. • Symptoms may persist into adulthood • Effective intervention early in childhood may alter course of ADHD, decreasing conduct disorder as an adolescent and antisocial personality disorder with its various complications (e.g., alcohol and drug abuse, criminality) as an adult. • Pharmacological treatment usually discontinued when a child reaches puberty, because adolescents presumably are more prone to abuse amphetamine-like drugs. • Growth-reducing effects blunt adolescent growth spurt (even with "summer holiday" from drug). • Drugs improve behavior and learning ability in 50-75% of ADHD children Psychostimulants used to treat ADHD Feature Methylphenidate Pemoline d-amphetamine Elimination half-life 2-3 2-12 6-7 Time to peak plasma 1-3 1-5 3-4 Onset of behavioral effect 1 week 3-4 weeks 1 week Duration of behavioral 3-4 not available 4 effect Dailv dose range mg/kg/day 0.6-0.7 0.5-3.0 0.3-1.25 mg/day 10-60 38-113 5-40 • Methylphenidate has rapid onset and short duration; thus must be administered at both breakfast and lunchtime • Pemoline has longer but variable half-life; disadvantages: slow onset and reduced level of therapeutic efficacy. • Dextroamphetamine rarely used for ADHD...however can be useful in non-respondents to methylphenidate or pemoline. • Antidepressants not widely used for ADHD, but one, nortriptyiine, has been studied Amphetamines and Obesity • Impediments: side effects, dependency, addiction, and rapid tolerance. • Small amounts of weight loss (<1 pnd/wk) accompany use; effects lost after only few weeks • Anorexics: benzphetamine (Didrex), phendimetrazine (Anorex, Oblan, Phendiet, Wehless), diethylpropion (Tenuate, Tepanol), mazindol (Mazenor, Sanorex), phentermine (Fastin, lonamin, Phentrol, Adipex-P, ObyTrim), phenylpropanolamine (Dexatrim), and d- amphetamine/amphetamine combination (Obcontrol). • Search continues for amphetamine-related derivatives that suppress appetite without potential for drug abuse and without concomitant development of tolerance. • New drugs (fenfluramine, fluoxetine, and sertraline) related to amphetamine but act to potentiate serotonin neurotransmission rather than dopamine. • Fenfluramine (Pondimin), partially inhibit serotonin reuptake and facilitate its release. • Fenfluramine combined with phentermine (dopamine releaser) enhanced weight loss over what could be achieved with behavior modification, exercise, and nutrition program, and effect sustained over 4 yrs (discontinued) • Fluoxetine and sertraline are serotonin reuptake inhibitors that are clinical antidepressants...both drugs produce satiety and reduce food intake; tolerance to anorectic effect after several weeks Nasal Decongestants (ND) • Structurally related to amphetamine, they alter synaptic actions of norepinephrine both in brain (minor effects) and in peripheral nervous system (more potent in PNS). • ephedrine, tetrahydrozoline (Tyzine), metaraminol (Aramine), phenylephrine (Neo-Synephrine), pseudo-ephedrine (Sudafed), xylometazoline (Otrivin), nylidrin (Arlidin), propylhexedrine (Benzedrex), phenmetrazine (Preludin), naphazoline (Privine), oxymetazoline (Afrin). • After use, compensatory rebound increases nasal stuffiness, similar to cocaine stuffy nose • Ephedrine is active ingredient in illicit preparations alleged to be amphetamine. "ICE" a Free Base Form of Methamphetamine (crank, crystal, and speed) • More potent than amphetamine and easily synthesized in clandestine labs from inexpensive chemicals (ephedrine), making large amounts available at low cost. • In animals, implicated as a neurotoxic agent; such toxicity not yet demonstrated in humans • When converted to base form (ICE) methamphetamine can be vaporized and inhaled in smoke. • Abuse of ICE began in Hawaii, spread to Japan (where it is called shabu), then to California, and dispersed everywhere. • Since not injected, smoking removes guilt feelings, needle marks, infection risk, evidence of drug use, and heavy drug impressions associated with injection of illegal drugs. Methamphetamine Pharmacokinetics • Rapid absorption into plasma which abates over 4 hrs and then progressively declines in plasma levels thereafter...~90% eventually reaches plasma. • Biological half-life over 11 hrs....after distribution ~60% slowly metabolized in liver and excreted through kidneys, along with unmetabolized methamphetamine (~40% excreted unchanged). • Thus, long action follows from slow and incomplete metabolism; in contrast, cocaine is rapidly and completely detoxified by enzymes found in both plasma and liver. Methamphetamine Effects and Toxicity • Indistinguishable from cocaine...potent psychomotor stimulant and positive reinforcer. • Repeated high doses associated with violent behavior and paranoid psychosis...such doses cause long-lasting decreases in brain dopamine and serotonin. • Changes are irreversible, since chemical effects persist for >year • Permanent neurochemical changes: alterations in sleep, sexual function, depression, movement and/or schizophrenia. • Acute delusional and psychotic behavior occurs after smoking ICE...however, unlike cocaine, ICE- induced psychosis persists for days or weeks • Fatalities result from cardiac toxicity manifested as pulmonary edema or heart failure. HALLUCINOGENS • Psychedelic drugs (PD’s): group of compounds that induce visual and auditory hallucinations. • Disturb cognition and perception and behavior similar to that in psychotics. • Naturally occurring PD’s used for thousands of years for effects on sensory perception. • Prior to 60s, PD’s were restricted to religious rituals • During late 60s-70s, psychedelic agents used to enhance perception, expand reality, promote personal awareness, and induce comprehension of spiritual or supernatural. • Structures resemble acetylcholine, two catecholamines (norepinephrine and dopamine), and serotonin. • Structural similarities lead to 3 classes of psychedelics: 1. Anticholinergic psychedelics: intoxication, amnesia, and delirium by blocking postsynaptic acetylcholine receptors. 2. Catecholamine-like act by influencing a subset of catecholamine and serotonin receptors. 3. Serotonin-like psychedelics: act by influencing a subset of serotonin receptors. 4. Psychedelic anaesthetics: block glutamate NMDA receptor calcium ion conductance. Classification of Psychedelic Drugs ANTICHOLINERGIC PSYCHEDELIC DRUGS Atropine and Scopolamine CATECHOLAMINE-LIKE PSYCHEDELIC DRUGS Mescaline, DOM (STP), MDA, MMDA, TMA, DMA, MDMA, Myristin, elemicin SEROTONIN-LIKE PSYCHEDELIC DRUGS LSD, Dimethyltryptamine (DMT), Psilocybin, psilocin, bufotenine Ololiuqui (morning glory seeds) Harmine PSYCHEDELIC ANESTHETIC DRUGS Phencyclidine (Angel Dust, Sernyl), Ketamine (Ketalar) Anticholinergic Psychedelic Drugs (A-PD’s) Historical Background • Scopolamine and atropine block muscarinic acetylcholine receptor sites, and have no intrinsic activity. • Distributed widely in nature in plant Atropa belladonna (as belladonna or deadly nightshade), in Datura stramonium (Jamestown weed, jimsonweed, stinkweed, thorn apple, or devil's apple) and Mandragora officinarum (mandrake). • Used in Middle Ages as source of poison (nightshade). • Atropa belladonna, derived from Atropos, Greek goddess who cut the thread of life. • Belladonna means "beautiful woman," which refers to ability to dilate pupils when it is applied topically to eyes. • Delirium caused by these substances may have persuaded certain persons that they could fly-that they were witches. • Used in World War II as truth-serum. • Cigarettes made from Datura stramonium and Atropa belladonna sold in pharmacies until the 70s to treat asthma. A-PD Pharmacology • Act on PNS to depress salivation and sweating, increase temperature, dilate pupils, blur vision, and increase heart rate. • Atropine poorly crosses blood-brain barrier, thus scopolamine is primary CNS-active intoxicant. • Low doses: drowsiness, mild euphoria, profound amnesia, fatigue, delirium, mental confusion, dreamless sleep, attention loss, clouds consciousness and produces amnesia; it does not expand sensory perception. • High doses: behavioral state resembles toxic psychosis... CNS effects: delirium, mental confusion, sedation, and amnesia; PNS effects: tachycardia, blurred vision, urinary retention, and dry mouth. Catecholamine-like Psychedelic Drugs (C-PD’s) • Methoxylated amphetamine derivatives: mescaline, DOM (also as STP), TMA, MDA, MDMA (ecstasy), MMDA, DMA, and drugs from nutmeg (myristin and elemicin). • Compared to amphetamines/cocaine: more intense psychedelic action and less intense behavioral stimulant action. • C-PD’s produce similar effects: sensory perceptual (time) distortion; altered color perception, sounds, shapes; complex hallucinations and synesthesia; dreamlike feelings; depersonalization; altered affect (depression or elation); and somatic effects (tingling skin, weakness, tremor, etc.). Mescaline • Peyote (Lophophora williamsii) common plant in southwestern U.S. and Mexico; spineless cactus with small crown, or "button," and long root. When used for psychedelic purposes, crown is cut from cactus and dried into hard brown discs (mescal button); active compound is mescaline. Mescaline - Historical Background • Pre-Columbian times, when cactus was used in religious rites of Aztecs and other Mexican Indians. • Legally available for religious practice of Native American Church of North America-an organization that claims some 250,000 members from Indian tribes throughout North America. 1896 mescaline identified as active ingredient in peyote. • Variety of mescaline derivatives synthesized; all have methoxy (OCH3) groups or additions on benzene ring • Methoxylation results in high affinity for presynaptic serotonin receptors and exert LSD-like psychedelic effects. Mescaline Pharmacology • Orally: Transport to brain in 30-90 mins...effects persist for ~10 hrs...not metabolized before it is excreted. • Low doses: (2-3 mgs/kg) produce amphetamine-like behavioral effects and include: pupil dilatation, increased blood pressure and heart rate, increase body temperature, EEG and behavioral stimulation. • Usual oral dose: (5 mg/kg) causes: anxiety, sympathomimetic effects, hyper-reflexia of limbs, static tremors, and vivid hallucinations of brightly colored lights, geometric designs. Synthetic Amphetamine Derivatives • DOM, MDA, TMA, MDMA, MMDA, and DMA structurally related to mescaline and methamphetamine and more potent and toxic than mescaline • Produce similar effects: low doses amphetamine-like effects, high doses LSD-like serotonin-mediated effects DOM (or STP for "serenity, tranquillity, and peace") • Effects similar to mescaline: doses 1-6 mgs produce euphoria, followed by 6-8 hr period of hallucinations. • 100x more potent than mescaline but less potent than LSD. • High incidence of overdose; acute toxic reactions; tremors leading to convulsive movements, followed by death. MDA, MMDA, TMA • Effects resemble mescaline and LSD: reflect mix of catecholamine and serotonin interactions. • MDMA ("ecstasy") resembles MDA but less hallucinogenic, with less sense of disembodiment and visual distortion • MDMA releases serotonin and cause acute depletion of forebrain serotonin and destruction of serotonin neurons...serotonergic systems are implicated in control of sleep, food intake, sexual behavior, anxiety, and mood, disruption due to cell loss could have major consequences. Myristin and Elemicin • Active ligand in nutmeg and mace related to mescaline • From dried seed and seed coat of East Indian nutmeg tree (Myristica fragrans) • Ingestion of large amounts (I-2 teaspoons, usually brewed in tea), after 2-5 hr delay, induce euphoria and changes in sensory perception, visual hallucinations, acute psychotic reactions, and feelings of depersonalization and unreality. • Unpleasant side effects: vomiting, nausea, and tremors. Serotonin-like Psychedelic Drugs (S-PD’s) • S-PD’s include: 1. lysergic acid diethylamide (LSD) 2. psilocybin and psilocin (mushroom Psilocybe mexicana), 3. dimethyltryptamine (DMT), and 4. bufotenine • LSD is partial serotonin2 (5-HT2) receptor agonist: triggers responses involving other neurotransmitter systems (hence, overlap between serotonin and catecholamine psychedelics). • S-PD’s alter mood and perception via activation of serotonin cells in pontine raphe (a neuronal filter for sensations and perceptions, eliminating those that are unimportant, irrelevant, or commonplace). • Adverse reactions: paranoid ideation, depression, undesirable hallucinations, and/or a confusional state resembling a drug-induced dementia. • Serotonin receptor blockers are useful in antagonizing psychedelic effects "bad trip". • Antipsychotic drugs with antiserotonergic properties used to treat LSD-induced psychosis...however, not routinely used because neuroleptics evoke motoric side effects LSD - Historical Background • 1938 synthesized by Albert Hoffman, Swiss chemist, as part of an organized research program to investigate therapeutic uses of compounds obtained from ergot. • Ergot: natural product from fungus (Claviceps purpurea), which grows on rye in grain fields of Europe and North America...active agents are derivatives of lysergic acid. • Pharmacological actions of ergots: constriction of blood vessels and increased contractions of uterus (at least at low doses). • Ergot alkaloids used for migraine headaches and control postpartum hemorrhaging. • From 1938 until 1943 LSD remained on laboratory shelf unnoticed, when Doctor Hoffman had an unusual experience: In the afternoon of 16 April 1943...I was seized by a peculiar sensation of vertigo and restlessness. Objects, as well as the shape of my associates, appeared to undergo optical changes. I was unable to concentrate on my work. In a dreamlike state I left for home, where an irresistible urge to lie down overcame me. I drew the curtains and immediately fell into a peculiar state similar to drunkenness, characterized by an exaggerated imagination. With my eyes closed, fantastic pictures of extraordinary plasticity and intensive color seemed to surge toward me. After 2 hours this state gradually wore off. " Hoffman ingested compound under controlled conditions and described experience with a dose now known as ~10x the dose required to induce psychedelic effects...as a result: After 40 minutes, I noted the following symptoms: slight giddiness, restlessness, difficulty in concentration, visual disturbances, laughing.... Later, I lost all count of time. I noticed with dismay that my environment was undergoing progressive changes. My visual field wavered and everything appeared deformed as in a faulty mirror. Space and time became more and more disorganized and I was overcome by a fear that I was going out of my mind. The worst part of it being that I was clearly aware of my condition. My power of observation was unimpaired.... Occasionally, I felt as if I were out of my body. I thought I had died. My ego seemed suspended somewhere in space, from where I saw my dead body lying on the sofa.... It was particularly striking how acoustic perceptions, such as the noise of water gushing from a tap or the spoken word, were transformed into optical illusions. I then fell asleep and awakened the next morning somewhat tired but otherwise feeling perfectly well. • 1949 first study of LSD in humans conducted in U.S., and during 50s large quantities of LSD distributed to pharmacologists and physicians worldwide for research • LSD tried as adjunct to psychotherapy to help patients verbalize problems; this has not proven to be effective. • Early work on human volunteers introduced LSD to college campuses, from there, to a wider audience...reached peak in popularity in late 60s, after which use has decreased LSD Pharmacokinetics • LSD often added to other substances, such as squares of paper, backs of stamps, or sugar cubes and taken orally...usual doses range 25-300 micrograms and absorbed in ~1hr reaching peak in 3hrs and subsiding in 6-8 hrs. • Distributed rapidly in body, brain and crosses placenta; liver metabolized; detected in urine by radioimmunoassay LSD Physiological Effects • Slight increase in body temperature, pupil dilatation, increased heart rate and blood pressure, increased blood glucose levels, dizziness, drowsiness, and nausea. • Low level of toxicity...effective dose 50 microgms and lethal dose of 14 milligms...therapeutic ratio of 280 LSD Psychological Effects • Unpredictable and influenced by variety of factors: personality, expectations, previous experience with LSD and other psychoactive drugs, motivations for using drug, drug setting, and persons with whom user interacts • Predictable responses: alterations in mood and emotion, laughter or sorrow evoked easily; euphoria and dysphoria • Principal psychological effects: perceptual changes, especially visual hallucinations and perceptual distortions...true auditory hallucinations rare. • Psychedelic experience can be divided into three phases: 1. Somatic phase consists of CNS stimulation and autonomic changes predominantly sympathomimetic. 2. Sensory phase characterized by sensory distortions and pseudo-hallucinations, effects desired by user. 3. Psychic phase signals maximum drug effect where changes in mood, disruption of thought processes, altered perception of time, depersonalization, true hallucinations, and psychotic episodes (bad trip) occur. LSD Tolerance and Dependence • Tolerance develops rapidly, and cross-tolerance occurs between LSD and other C-PD’s and S-PD’s. • Physical dependence does not develop, even when drug is used repeatedly or for prolonged period of time...no withdrawal signs exhibited...animals do not self-administer. LSD Adverse Reactions and Toxicity • Fall into four categories: 1. effects on the psychological state of the user 2. possibility of permanent damage to the brain 3. possible effects on the fetus when the drug is taken by a pregnant woman, and 4. deleterious effects on society if use of drug were widespread. • LSD eliminates normal defence mechanisms, and thus precipitates psychotic episodes. • Persistent flashbacks occur weeks/months after last drug use...mechanism unknown (15% of users)...precipitated by use of marihuana, anxiety, fatigue, or movement into a dark environment, flashbacks persist intermittently for several years. • Psychedelics can precipitate serious depressions, paranoid behavior, or prolonged psychotic episodes. LSD-like Tryptamine Derivatives Dimethyltryptamine (DMT) • Naturally occurring psychedelic related to serotonin. • Binds to 5-HT2 receptors and active ingredient of South American snuff, such as cohoba (prepared from beans of Piptadenia peregrina) and epena (prepared from bark of trees found in upper Amazon River valley), as well as vopo. • Presence of bufotenine (from the frog Bufo containing 5-hydroxy-DMT in its skin) also contributes to effect. • DMT not absorbed orally; must be smoked or sniffed Duration of action short, ~1 hr ("business man's LSD"). Psilocybin (4-phosphoryl-DMT); psilocin (4-hydroxy-DMT) • Psychedelic agents found in 15 species of mushrooms that belong to the genera Psilocybe, Panaeolus, and Conocybe that grow throughout world, including Central America and northwestern portion of U.S. Psilocybe mexicana (teonanacatl, or "God's flesh") long history as sacramental in Central America. ~1/200 as potent as LSD; effects last 6-10 hrs • Psilocybe intoxication described in 1955 by Gordon Wasson, New York banker, when he traveled through Mexico to participate in a Psilocybe ceremony...Wasson said: It permits you to travel backwards and forward in time, to enter other planes of existence, even to know God...Your body lies in the darkness, heavy as lead, but your spirit seems to soar and leave the hut, and with the speed of thought to travel where it listeth, in time and space, accompanied by the shaman's singing...at least you know what the ineffable is, and what ecstasy means. Ecstasy! The mind harks back to the origin of that word. For the Greeks, ekstasis meant flight of the soul from the body. Can you find a better word to describe this state?" Ololiuqui (morning glory seeds) • Naturally occurring; used by Central and South American Indians as intoxicant and hallucinogen...seeds contain lysergic acid amide (not lysergic acid diethylamide, LSD). Lysergic acid amide identified as ~0.1 as active as LSD • Side effects: nausea, vomiting, headache, increased blood pressure, dilated pupils, sleepiness, etc. • Ingestion of >100 seeds: sleepiness, distorted perception, hallucinations, and confusion....flashbacks reported Harmine • Seeds of Peganut harmala; plant native to the Middle East. Seeds used as intoxicants for centuries and evokes hallucinations accompanied by nausea, vomiting, sedation, and finally sleep. Psychedelic Anesthetic Drugs: Phencyclidine and Ketamine • Structurally unrelated to other psychedelic and psychoactive drugs and do not act on serotonin neurotransmission. • PCP receptor activation: amnesia, analgesia, and psychedelic dissociation. • 1956: developed as potent analgesic-amnestic anesthetic • Used briefly as anesthetic in humans; high incidence of serious psychiatric reactions, including agitation, excitement, delirium, disorientation, and hallucinatory phenomena. • Ketamine: related to PCP, induces anaesthetic state in low doses with moderate incidence of psychiatric side effects...occasionally in in patients who cannot tolerate cardiovascular depressant effects of other anesthetics. • Early 70s referred to as "peace pill" (PCP)...appeared on illicit market in form of powder, tablets, leaf mixtures, and "rock" crystals and sold as "crystal," "angel dust," "hog," "PCP," "THC," "cannabinol," or "mescaline." PCP Pharmacokinetics and Mechanism of Action • Absorbed orally or smoked; peak effects in ~15 min, metabolized in liver...elimination half-life ~18 hrs but varies because of enterohepatic recirculation. • Brain binding sites: anterior forebrain (neocortex and olfactory structures), hippocampus, dorsal spinal cord. • Noncompetitive antagonism of NMDA-glutamate receptor; mediates analgesic, psychotomimetic and amnesic effects; involved in synaptic plasticity and long-term synaptic efficacy (long-term potentiation) • NMDA/PCP receptor complex: composed of 4 membrane-spanning peptides which cluster together to form ion channel that resembles the benzodiazepine-GABA receptor...PCP receptor located within lumen of the ion channel. PCP Psychological Effects • Dissociative anesthetics and induce: unresponsive state with intense analgesia and amnesia, blank stare • Low doses: mild agitation, euphoria, disinhibition, or excitement with blank stare, rigidity, unable to speak, and unresponsive to pain, including unpredictable violent reactions to environmental stimuli. • Acute PCP toxicity: withdrawn psychotic state, autistic, negativistic, unable to maintain cognitive set, manifest bizarre responses to projective testing, and catatonic posturing. • High doses: coma or stupor...abusers tend to "titrate" dose to max effect while attempting to avoid unconsciousness; recovery within 2-4 hrs, although confusion lasts 8-72 hrs. • Overdoses: (1 gm) prolonged periods of stupor or coma lasting several days, marked by intense seizure activity, increased blood pressure, and respiratory depression often fatal...recovery marked by confusion and delusions lasting >2 weeks...followed by psychosis lasting several weeks-months. PCP Side Effects and Toxicity • Schizophrenia-like psychotic state; Flashbacks due to mobilization of stored PCP from adipose tissues • Intoxicated state: severe anxiety, aggression, panic, paranoia, and rage...also violent reactions to sensory input, leading to falls, drowning, burns, driving accidents, and aggression, resp. depression, seizure activ. pulmon. edema • Self-inflicted injuries and injuries sustained while physical restraints are applied are frequent, and analgesic action contributes to lack of response to pain. PCP Tolerance, Dependence, and Abuse • Only psychedelic drug self-administered by monkeys and man, suggesting brain reward area involvement and thus risk of compulsive abuse despite negative health consequences. Tolerance develops in lab animals, with 2-fold dose increase • Withdrawal poorly studied in man; animals given unlimited access to PCP for 1 month or longer demonstrate withdrawal. • Therapy for PCP intoxication aimed at reducing systemic level of drug, keeping individual calm and sedated, and preventing any severe adverse medical effects. • Therapy involves: 1. Minimization of sensory inputs by placing intoxicated individual in a quiet environment 2. Oral administration of activated charcoal, which binds PCP in stomach and intestine 3. Precautionary physical restraint to prevent self-injury 4. Sedation with either benzodiazepine (e.g. lorazepam) or neuroleptic (e.g. haloperidol). 5. Hyperthermia, hypertension, convulsion, renal failure, and other medical consequences treated as necessary...psychotic states long lasting (several weeks), especially in individuals with schizophrenia.
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