1 Drugs of abuse Dr. Martha Nowycky Nov. 27, 2017

2 Final Exam Review Session Thurs., Dec 7 4:00-5:30 B-552

3 Learning objectives Define physical dependence, withdrawal, addiction, tolerance Describe major classes of drugs of abuse and how they differ in major effects on behavior Understand mechanism of action of individual drugs at receptor level Describe the role of the ‘reward pathway’ in addiction Understand how pharmacokinetics and pharmacodynamics affects the effects of closely related drugs (e.g. agonist, antagonist and mixed agonist-antagonists opioid drugs, methamphetamine vs amphetamine, heroin vs. morphine) Understand basis of poly-drug toxicity

4 Lecture Outline Drug Abuse: definitions & pharmacological characteristics – Drug of Abuse – Addiction – Dependence – Physical and Psychological – Withdrawal – Tolerance Mechanism of action – neurotransmitter systems Dopamine reward pathway theory of addiction Major classes of drugs of abuse – General CNS depressants (alcohol, benzodiazepines, barbiturates) – Specific CNS depressants: Opioid Analgesics – CNS Stimulants (Cocaine, Amphetamine, MDMA, Nicotine) – Hallucinogens (LSD, Marijuana) Poly-drug toxicity

5 Drug Abuse: definition Drug abuse: persistent self-medication of a drug in chronically excessive quantities without due regard for accepted medical practice or harm caused to self or society. – Almost all of drugs of abuse act on CNS affecting mood, feeling & behavior – Exceptions: e.g. steroids, performance enhancing drugs

6 Mood-altering drugs of abuse Most act on brain (CNS) and some act on Peripheral Autonomic Nervous System (PNS) All interact with natural neurotransmitter systems Most (but not all) are addictive Most (but not all) cause psychological dependence Most (but not all) result in physical dependence / withdrawal symptoms Most (but not all) exhibit tolerance

7 Major classes of mood-altering drugs of abuse CNS Depressants GENERAL DEPRESSANTS: – Alcohol – Barbiturates – Benzodiazepines SPECIFIC DEPRESSANT: – Opiates / opioids CNS Stimulants – Cocaine – Amphetamines – MDMA (Ecstasy) – Nicotine Hallucinogens – LSD – Marijuana

8 Compulsive, deliberate behavior in seeking out a drug, despite negative consequences on health, family, friends, and/or job. – User ‘loses control’ over the drug smokers, alcoholics, heroin addicts Addiction has a strong biological component – in humans it may have a psychological component as well Addiction: definition

9 Addiction is mainly a biological process Rats and other laboratory animals self-administer addictive drugs of abuse In humans, there may be an additional component of psychological dependence

10 – Strong emotional or motivational drive to take drug – When drug is discontinued, individual may exhibit emotional symptoms of withdrawal such as dysphoria (a state of unease or dissatisfaction) and anhedonia (decreased ability to experience pleasure), or anxiety – Psychological dependence contributes to addiction, but an individual can be psychologically dependent without behaving in self-destructive ways Psychological dependence: definition

11 Physical dependence and withdrawal: definition Physical dependence: altered adaptive physiologic state seen after repeated administration of drug. Body incorporates substance into its ‘normal’ functioning. It tries to compensate in some way to counter drug effect – Revealed when drug is abruptly withdrawn Withdrawal or abstinence syndrome – Physical and psychological symptoms experienced when reducing or discontinuing a substance that body has become dependent on – Withdrawal often produces effects opposite to drug effects E.g. Xanax: anti-anxiety drug, WD = anxiety & seizures – Withdrawal often so unpleasant or life-threatening that it becomes part of drug-seeking behavior

12 Addiction: summary Addiction is a biological process but has strong psychological components Depends on individuals – personality factors, life history, underlying psychiatric disease Some drugs are more addictive than others Some individuals more susceptible than others Conditions, motivation are hugely important – E.g. after liver transplant surgery, patients take mega- doses of opiates for months but rarely become addicted, although they are physically dependent (undergo withdrawal symptoms if opioids stopped)

13 Drug Tolerance: definition Tolerance = condition of decreased responsiveness after prior or repeated exposure Successive doses have to be increased to produce equal effects or durations Tolerance disappears (is reversed) when administration is discontinued Dose D e s i r e d E f f e c t

14 Tolerance – Characteristics of drug tolerance: – Rate for developing tolerance depends on the particular drug, dosage, and frequency of use – Different effects of the same drug may develop different amounts of tolerance over different time courses. – Reversible – dose returns to initial level after period of weeks or months without drug – Pharmacokinetic Tolerance: - – E.g. Increased metabolism: less drug reaches site of action. – Pharmacodynamic Tolerance: (Reduced responsiveness) – Drug effect is decreased by cellular mechanisms. For example, there may be a down regulation of receptor numbers or increased activity in compensating systems

15 Pharmacokinetic Tolerance can be overcome by more drug – Pharmacodynamic tolerance usually cannot Log (Dose) Response Log (Dose) Response Pharmacodynamic Pharmacokinetic

16 Addiction can occur without physical dependence – Individual may be addicted to cocaine or marijuana but experience only mild physical WD symptoms Tolerance and physical dependence can occur without addiction – Cancer patients may take enormous quantities of opioids for pain without becoming addicted. But they undergo physical withdrawal symptoms if drug is terminated. – LSD – develop very strong tolerance, but no addiction Physical dependence can be a powerful factor in reinforcing addiction – Opioid or alcohol withdrawal are very unpleasant and contribute to drug craving Drug Addiction / Physical Dependence / Tolerance can occur independently of each other

17 DRUGS OF ABUSE MODULATE ACTIVITY OF NATURAL NEUROTRANSMITTER SYSTEMS IN BRAIN AND PERIPHERAL NERVOUS SYSTEMS

18 3 TYPES OF DRUG RECEPTORS FOR DRUGS OF ABUSE 1. Ligand-gated ion channels e.g. benzodiazepines (Valium) on GABA channels 2.GPCR – G Protein Coupled Receptors e.g. opioids; cannabinoids Drugs may be agonists, antagonists, mixed agonists-antagonists or allosteric modulators of neurotransmitter receptors 3. Neurotransmitter transporters Drugs modify neurotransmitter availability by interacting with monoamine and catecholamine uptake transporters e.g. cocaine, amphetamine

19 Common ligand-gated ion channels that are targets of drugs of abuse – GABA – inhibitory – Glutamate – Excitatory – ACh – Excitatory (nicotine)

20 Common GPCR that are targets of drugs of abuse – Opioid GPCR – Serotonin GPCR – Cannabinoid GPCR N C N 67PW67PW P YP Y N C 12345DPPW12345DPPW C C DRYDRY

21 Neurotransmitter (NT) transporters NT transporters are the means for terminating the action of some NT Located on the presynaptic side, transporters take up released neurotransmitters Block of NT transporters increases amount of NT – E.g. Cocaine blocks dopamine transporter (DAT) Transporters which are targets of drugs of abuse take up monoamine neurotransmitters

22 Do not memorize structures – but learn names of transmitters

23 NEUROTRANSMITTER SYSTEMS – PATHWAYS IN BRAIN A neuron typically makes and releases one primary neurotransmitter Neurotransmitter pathways consist of a group of neurons using same neurotransmitter and sending messages long-distance to one or a few target areas

24 Monoamine pathways have cell bodies in small areas of midbrain or brainstem and project widely throughout much of brain, affecting aspects of overall brain activity. They are targets of several drugs of abuse. DA plays important role in addiction.

25 Dopamine ‘Reward Pathway’ theory of addiction Almost all drugs of abuse, except hallucinogens, interact with brain’s ‘reward pathway’ ventral tegmental area VTA DA Reward pathway is a dopaminergic (DA) projection from ventrotegmental area (VTA) of hypothalamus to nucleus accumbens, part of forebrain limbic system and to prefrontal cortex

26 Dopamine ‘Reward Pathway’ theory of addiction Physiologic role of VTA: pathway reinforces mechanisms and behavioral adaptations for body functions such as getting food, water, sex Activation of this pathway accounts for the “ positive reinforcement ” feeling and makes us want to continue the action that triggered that feeling until the original urge or need is satisfied.

27 Dopamine Theory of Addiction - Reward Pathway Addictive drugs, directly or indirectly increase dopamine, hijacking the reward system and leading to maladaptive addiction pathway. Rats and monkeys self-administer drugs that are positively reinforcing and addictive in humans either iv or through cannula directly into VTA reward pathway.

28 Biological aspect of addiction Rats self-administer addictive drugs of abuse into VTA ‘reward’ center in hypothalamus SELF-ADMINISTERED:NOT SELF-ADMINISTERED: Fluoxetine (Prozac) LSD Mescaline Psilocybin – Alcohol – Amphetamines – Barbiturates – Caffeine – Cocaine – Diazepam (Benzodiazepine) – Gamma-hydroxybutyrate – Heroin – MDMA (Ecstasy) – Morphine – Nicotine – Phencyclidine (PCP) – THC - Marijuana Table 15-1, Levine, Ed 7 Bold face indicates drug covered in this lecture

29 Katzung et al, Clinical Pharmacology, 11 th edition. Drugs of abuse act at various sites in reward pathway: all increase DA release in accumbens VTANucleus accumbens Opioids act on GPCR of GABA neurons Benzodiazepines, nicotine act on ion channels Cocaine, amphetamines act on transporters All increase dopamine

30 Game plan for rest of lecture CNS depressants, stimulants and hallucinogens – Clinical picture – short and long-term effects – Mechanism of action – receptors & systems – Pharmacodynamics – drug-receptor interactions Agonists, mixed agonist-antagonists, pure antagonists – Pharmacokinetics – how distribution or metabolism can influence clinical effects

31 CNS DEPRESSANTS

32 Drugs of Abuse: CNS DEPRESSANTS GENERAL CNS DEPRESSANTS: Mechanism of action – Enhance activity of the GABA-gated Cl - channel Examples – Ethyl alcohol – Barbiturates – Benzodiazepines SPECIFIC CNS DEPRESSANTS: Opioids Mechanism of action – Stimulate opioid receptors (GPCR) Examples – Morphine – Heroin – Oxycontin

33 General CNS depressants modulate GABA A receptor activity and decrease overall level of excitation in brain

34 GABA is the major inhibitory neurotransmitter in the brain GABA A receptors are Cl - conducting ion channels GABA is typically found in small interneurons in every part of CNS IPSPIPSP Time (ms) Cl - GABAGABA

35 Example: Valium (a benzodiazepine) is an allosteric modulator of GABA A receptors and potentiates GABA-triggered currents General CNS depressants modulate GABA receptor activity in various ways. Influence strength of GABA transmission.

36 General CNS Depressants: alcohol, barbiturates, benzodiazepines Actions and properties – Enhance activity of the GABA-gated Cl - channel – Decrease anxiety and tension, produce sedation – Act on circuitry of reward system - produce physical and psychological addiction – Act on RAS – Reticular Activating System – Withdrawal symptoms are similar for all general CNS depressants

37 CNS depressant effects on Reticular Activating System (RAS) Reticular Formation (RF): primitive brainstem region that receives sensory inputs, contains respiratory (breathing) centers, and coordinates levels of motor activity and CNS arousal RAS: pathway that arises in RF and fans out across brain RF - RAS can excite or inhibit specific areas of cortex RF has low intrinsic activity – in absence of sensory impulses is quiet; individual relaxed, drowsy, or asleep RF receives sensory stimuli; ‘arouses’ brain Alcohol, barbiturates, general anesthetics act through GABA receptors to depress activity in RF and RAS

38 CNS depressants: actions on RAS – Behavioral responses to drugs depend on which part of pathway is depressed and degree of CNS excitability Depends on environment and personality – In social setting, cortex may be uninhibited – effects look like stimulation – Paradoxical excitement –talkativeness, vivacity, self-confidence, loss of self-restraint – Accompanied by loss of mental acuity and judgment and impaired motor coordination As dose is increased get more of depressive symptoms: – Slurred speech; staggering; loss of balance and falling; loss of emotional control; stupor; severe respiratory depression; finally coma and death

39 Ethanol strongly enhances the inhibitory effects of GABA at GABA A receptors Depression of higher faculties of the brain and loss of inhibitions with free release of emotions (cheerfulness, euphoria, talkativeness, sexual assaults & violence). Mild intoxication leads to motor incoordination, slowing of reaction time, sleepiness. – Smell of alcohol, flushing of the face due to vasodilation of blood vessels of nose & conjunctiva; Slurred speech, vestibular disturbance, tremors of the hand. Tolerance and physical dependence: induction of alcohol dehydrogenase and desensitization and decrease of GABA A receptors. 1.Ethyl Alcohol

40 Receptor Regulation – Source of withdrawal symptoms Glutamate GABA GABAGlutamate Physiologic condition – balanced inputs from inhibitory GABA and excitatory glutamate pathways Alcohol intake – enhances GABA activity, creating disbalance in pathways Glutamate GABA In attempt to restore balance, get compensatory decrease of GABA receptors, increase of glutamate receptors. When deprived of alcohol, physical dependence (WD) – manifests as over-excitation

41 Withdrawal Syndrome – over-excitement of CNS – Begins within the first 24 hrs after abrupt withdrawal, reaches peak within 2-3 days, disappear within 1-2 weeks; – First days – headache, anxiety, involuntary muscle twitches, tremor of hands (shakes), weakness, insomnia nausea – Next days – worsening of symptoms – precipitous drop in blood pressure, tachycardia, fever, delirium with disorientation, delusions and vivid visual hallucination – Convulsions of grand mal seizure type – Can be fatal; more dangerous than opioid withdrawal – Fever, delirium tremens, and seizures may lead to 5–15% mortality if untreated.

42 Alcohol metabolism – major pathway is via Alcohol Dehydrogenase Intoxication and hangover symptoms

43 Long-term deleterious effects due to alcohol metabolism Unlike other drugs ethanol is a source of calories (i.e. food). Ethanol is metabolized through alcohol dehydrogenase and aldehyde dehydrogenase to acetate which enters the Krebs cycle, undergoes ketone body formation, or is synthesized into fatty acids. nutritional deficiencies especially thiamine. Fetal Alcohol Syndrome, major cause of mental retardation. alcohol dehydrogenase aldehyde dehydrogenase EthanolAcetaldehydeAcetateacetyl-CoA Intermediates (e.g. acetylaldehyde) can be damaging to cells throughout body. CNS: Cognitive defects and dementia through neuronal death. CVS: Cardiomyopathy, hypertension, dysrhythmias. GIeffects:-gastritis,pancreatitis,hyperlipidemia,cancer,fattyliver,cirrhosis, Do not memorize all symptoms!

44 2.Barbiturates Mechanism of action – Bind to GABA A - ion channel at a site distinct from benzodiazepines. Increase the duration of channel opening events. – Allosteric modulators of GABA activity Medical uses – Ultra short (Thiopental) are used as IV anesthetics. – Short-acting (Secobarbital) used for insomnia, pre-anesthetic sedation. – Long-acting(Phenobarbital)usedfortreatingepilepsyandchronic neurologic problems and assisted suicide. Recreational uses – Similar to alcohol – relaxed contentment and euphoria, anxiolytic Dangers – – Overdose due to respiratory suppression Do not memorize these drug names!

45 3.Benzodiazepines Mechanism of action – Bind to GABA A - ion channel at a site distinct from barbiturates. Increase the frequency of channel opening events. – Allosteric modulators of GABA activity Medical use – Anxiolytics, panic disorders, insomnia, seizures, alcohol withdrawal Advantages over barbiturates: – lower fatality, lower potential for abuse, but addictive in therapeutic doses Withdrawal symptoms – ‘Rebound’ – return of patient’s original symptoms, such as anxiety, but stronger – Similar to ethanol symptoms after chronic heavy use

46 Specific CNS depressants: Opioids Opioids have been used to relieve pain since ancient Egypt and ancient Greece Morphine is named for Morpheus, Greek god of sleep

47 Specific CNS depressants: Opioids Opium is a mixture of alkaloids extracted from the seed pods of papaver somniferum; Opium powder contains: ~10-12% morphine, 0.5-1% codeine

48 Opioid drugs act on family of opioid receptors: 7-transmembrane, G-protein coupled receptors Discovered in 1972 as proteins that bound 3 H-morphine Family of GPCR subtypes: e.g. Mu (  ) - Mu for morphine, Kappa (  ), Delta (  ) Normal function – receptors for endorphins and enkephalins

49 Opioid drugs produce a broad spectrum of physiological effects because opioid receptors are distributed in several parts of CNS as well as on smooth muscle of GI tract Opioids, acute effects: – Decrease pain perception – Produce euphoria, sensation of pleasure and indifference to problems – Often followed by mental dullness, drowsiness – Cause constipation by suppressing GI motility (direct action on smooth muscle of gut) – Cause miosis (pin-point pupils) At higher doses: – Affect endocrine function – Depress breathing (cause of overdose death)

50 Opioids, chronic use: – Rapid development of tolerance, physical dependence, addiction – Users chase feeling of euphoria – Tolerance assumes phenomenal proportions Addicts can take 5g daily (~500 x initial analgesic dose) Tolerance develops to most of opioid effects except to initial rush, constriction of pupil of eye, constipation

51 Addiction can come to dominate a users life The mortality rate for street heroin users is very high. Early death comes from – Involvement in crime to support the habit – Serious infections associated with non-sterile injection – Overdose Overdose death due to respiratory depression In pregnant female addicts, opioids easily crosses placenta – Congenital ‘morphinism:’ babies suffer withdrawal symptoms after delivery Consequences of chronic opioid use

52 Withdrawal / abstinence syndrome: “Drug dependence of morphine type” Symptoms appear shortly before next scheduled dose Without drug, symptoms intensify over several days; gradually subside over 7-10 days Severity depends on physical dependence Symptoms hit most major organs and systems – anxiety, restlessness, irritability, lacrimation, body aches, insomnia, perspiration, dilated pupils, gooseflesh (cold turkey), hot flushes, nausea, vomiting, diarrhea, fever, increased heart rate and bp, abdominal and other muscle cramps – Vomiting and diarrhea, combined with inability to retain water and food, lead to dehydration and loss of weight Symptoms unpleasant, but not as serious as for alcohol (rarely fatal) Do not memorize all symptoms!

53 All opioid drugs act on opioid receptors Differ in pharmacodynamics – Potency at various opioid receptors ( , ,  ) – Act as agonists, antagonists, or mixed agonist-antagonists (partial agonists) Differ in pharmacokinetics

54 Heroin (diacetylmorphine) Most lipophilic of all opioids – Acetyl groups at 3 and 6 hydroxy positions Heroin is morphine ‘pro-drug’ Morphine Heroin

55 Heroin (diacetylmorphine) Heroin crosses blood-brain-barrier rapidly; then hydrolyzed to morphine in the brain – Builds up higher concentration in brain – Must be injected iv – If taken orally, undergoes first pass metabolism and not as effective High brain concentrations are responsible for effects – ‘Rush’ – 3-4 times analgesic potency of morphine – Much more addictive than morphine – Withdrawal symptoms more intense than morphine

56 Oxycodone, OxyContin, and prescription oral painkillers Oxycodone is a semi-synthetic codeine analogue Potency and properties are similar to morphine Has full potency taken orally, unlike morphine Available since early 1900’s Useful for ambulatory (non-hospitalized patients)

57 OxyContin and prescription oral painkillers OxyContin© is trade name of slow-release version of oxycodone – Drug released over ~12 hrs – Introduced in 1995 – Within a few years (1996-2000) emergency room episodes involving oxycodone overdose tripled. Pill had high drug content and was abused by crushing and injection OxyContin and other oral painkillers are partially responsible for increased overdose and addiction in recent decades

58 Opioid mixed agonists-antagonists ( Opioid partial agonists) Definition: Drugs that act as agonists at some opioid receptors, but antagonists at others OR: Drugs that have agonist activity at low doses, antagonist activity at higher dose at same receptor Mixed agonists-antagonists used mostly for analgesic efficacy (agonist) – E.g. Buprenorphine. Agonist at low doses, then no effect at higher doses. Produces analgesic activity but less respiratory depression or addictive potential Called: a ‘ceiling effect’

59 Opioid agonists-antagonists: ‘ceiling effect’ Partial Agonist (Buprenorphine)

60 Opioid pure antagonists Naloxone and naltrexone – Both pure antagonists – prevent effects of agonist – Used to reverse overdose – Precipitate withdrawal in addicted individual with opioids on board

61 Opioid pure antagonists Naloxone and naltrexone have strikingly different pharmacokinetics – Naloxone (NARCAN) only effective in IV administration (strong first-pass hepatic metabolism) works in 1-2 min, short acting (1-4 hrs) Can be overcome by high concentrations opioid drugs in body once naloxone is metabolized Narcan available as a nasal spray – Naltrexone Given orally – unusually long-lasting (48-72 hrs), outlasts opioid drugs in body (can send patient home)

62 CNS STIMULANTS

63 CNS Stimulants 1.Sympathomimetic Stimulants (DA, NE, E, 5HT systems) – Cocaine – Amphetamines:dextro-amphetamine and methamphetamine – 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) 2.Nicotine (ACh agonist)

64 Stimulants increase activity in a variety of catecholamine, monoamine, and cholinergic systems Various drugs elevate mood, decrease fatigue, reduce appetite, promote feeling of well-being or even euphoria – Cortical stimulation – garrulousness, restlessness, increased motor activity, excitement Prolonged use nearly always followed by lethargy and mental depression CNS stimulants interact with reward pathway to increase DA release in VTA and/or n. accumbens – Amphetamines increase DA directly at terminals of VTA neurons – Cocaine prevents reuptake of DA in VTA – Nicotine increases firing rate of VTA neurons and DA release at VTA terminals CNS Stimulants

65 1.Cocaine Derived from leaves of Erythroxylon coca; Mechanism of action: In periphery, cocaine blocks Na + channels (original local anesthetic) and inhibits norepinephrine reuptake In brain, cocaine blocks dopamine reuptake in the VTA pathways by inhibition of DAT.

66 Cocaine – route of administration Oral route – slow absorption and distribution – almost no drug addiction – Erythroxylon coca in Andes – leaves are chewed or sucked – Usually used for religious rituals, fatigue, cold, only occasionally for individual enjoyment – Chronic toxicity or development of psychosis essentially unknown Routes of rapid delivery to CNS centers result in addiction – Cocaine HCl – crystalline powder that is snorted or injected iv Cocaine HCl decomposes when heated – Cocaine free base (crack). Can be smoked Cocaine free base melts at 93 o C – so can be vaporized by heating in a pipe. Vaporized drug reaches brain as fast as iv injection Smoking overcomes aversion people have to injection

67 Oral: low intensity, slow increase to peak levels, long duration Snorting (intranasal): peak 20 mins, duration ~ 60 mins. IV or smoking: peak in seconds to mins, duration 5-20 mins, intense effects. Method of cocaine absorption determines effects

68 Clinical Effects “ Rush ” : euphoria, alertness, feelings of elation, energy, feelings of competence, and increased sexuality followed by “ Crash; ” as drug effects subside: dysphoria, tiredness, mild depression; Acute toxic effects (overdose):seizures, hyperpyrexia, hypertension, respiratory failure, coma, and circulatory collapse Hallucinations, “ bugs creeping under skin with compulsive scratching ”, delirium, confusion, apprehension, and incoherence; Hyperactivity, feeling of great muscular strength, paranoid delusions, auditory and visual hallucination Prone to accidents since unaware of fatigue

69 Chronic use: Symptoms Cardiovascular & Cerebrovascular (due to sympathomimetic & Na + - channel blocking effects): – Arrhythmias, severe hypertension, angina or myocardial infarction. Stroke – (some of effects on cardiovascular system due to ion channel block in peripheral nerves and on cardiac cells) Personality changes, delusions, hostility, paranoia, psychosis & antisocial behavior Anorexia, weight loss Tolerance develops only to the euphoriant effect and not to its cardiovascular effects

70 Withdrawal symptoms Abrupt WD is not usually life-threatening Occur after several days of heavy use; reach a maximum in several days and then remit gradually over days or weeks. Symptoms: – Dysphoria, depression, irritability, lethargy, fatigue, prolonged sleep, lethargy, hunger; bradycardia (slow heart rate) – intensive craving may persist – increased risk of suicide.

71 2. Amphetamines Amphetamines elevate mood, combat fatigue, reduce appetite, increase general state of well-being Used as stimulants and appetite suppressants Mechanism of action – Centrally, increase synaptic dopamine by stimulating presynaptic release rather than by blockade of reuptake like cocaine – Peripherally, increase norepinephrine release

72 DA nerve terminal Cocaine – blocks DAT– causes DA build-up Amphetamine – enter nerve terminal through DAT – causes reverse flow of DA from vesicles and nerve terminals VMAT: vesicular monoamine transporter DAT: Dopamine transporter

73 2. Amphetamines Tolerance develops to effects most desired by addict – Addicts typically switch to iv rather than oral route – Tolerance develops slowly and reaches huge magnitudes – several hundred fold therapeutic dose Abrupt WD is similar to that of cocaine Amphetamines do not cause seizures & fatal arrhythmias typical of cocaine

74 3. Methamphetamine Clinical use – FDA-approved for treating ADHD and exogenous obesity (obesity originating from factors outside of the patient's control) in both adults and children Recreational use – Euphoric and stimulant properties Intravenous or smoked methamphetamine produces abuse syndrome similar to that of cocaine – Clinical deterioration may progress more rapidly – Behavior may become violent and unpredictable

75 Methamphetamine Much more dangerous and harmful than amphetamine Methyl group makes it more lipid soluble than amphetamine, enhances transport across BBB, makes it more stable against degradation by monoamine oxidase – a metabolizing enzyme Acts on DA, NE, and 5-HT transporters to reverse direction of flow – causing release of these transmitters into cytoplasm and from cytoplasm to synapse Potent neurotoxin, causing degeneration of DA and 5-HT cells ‘Meth mouth’ – teeth fall out. Caused by combination of poor oral hygiene, teeth grinding, excessive drinking of sweet bicarbonated drinks

76 Mechanism of action – Blocks both synaptic (DAT) and vesicular monoamine transporters (VMAT) – Has stimulant as well as hallucinogenic effects – Increases both dopamine release in reward pathway & serotonin Recreational use – Used orally at all-night parties known as “ raves ” – Intoxication is characterized by an initial “ rush, ” followed by a heightened sense of empathy or connectedness with others – effect is through release of hormone oxytocin Abrupt WD is similar to that of cocaine. – Users typically feel depressed, irritable and hungry Recent clinical trials in PTSD – post-traumatic stress disorder 4. MDMA, Ecstasy (3,4-methylenedioxymethamphetamine)

77 5. Nicotine Derived from the leaves of “ Nicotiana Tabacum ” plant.

78 Pharmacology: Mechanism of action: – Centrally, nicotine is an agonist of nicotinic cholinergic receptors (nAChR) and activates dopaminergic pathway, thereby increasing dopamine release at nucleus accumbens – Peripherally, nicotine activates nAChR in autonomic ganglia of sympathetic nervous system Effects – Euphoria, increased alertness, and elevated mood(CNS) – Tachycardia, increased blood pressure, and increased peristaltic activity, nausea and vomiting. (Peripheral nervous system - PNS) – Appetite decrease and loss of weight (CNS and PNS) Tolerance and physical dependencedevelop rapidly

79 Withdrawal Strong physiologic dependence – Smokers like to keep their blood levels of nicotine high throughout the day Withdrawal Symptoms – Craving, irritability, dysphoria, hostility, anxiety, difficulty concentrating, sleeplessness, increased appetite or weight gain Relapse after attempted cessation is very common – intense cravings and stress.

80 HALLUCINOGENS

81 Hallucinogens Definition: drug acting on CNS to produce hallucinations (false perceptions that have no basis in reality), alteration in thought, perception, or mood. Hallucinogens alter perception without causing sensations of reward and euphoria Pharmacologic characteristics and patterns of abuse of hallucinogens are individual – no common description. Often are not physically addictive Hallucinogens primarily target cortical and thalamic** circuits; addictive drugs primarily target VTA dopamine system. (** thalamus: region of brain that relays information from sensory systems to cortical areas)

82 Hallucinogens 5HT 2A (serotonin) GPCR agonists – LSD (lysergic acid diethylamide) – Psilocybin and psilocin (Aztec mushroom) – Mescaline (peyote cactus plant) CB1 GPCR agonists – Cannabinoids – active ingredient in marijuana Do not memorize italicized drugs

83 Lysergic acid diethylamide (LSD) – Acts as serotonin 5-HT 2A receptor agonists; 5HT 2A is a GPCR for serotonin Stimulation of 5HT 2A in cerebral cortex underlies distortions in cognition, perception, affect Produces visual hallucinations, alteration of color perception & strange patterns (user ‘sees’ music & ‘hears’ colors), depersonalization with sense of floating up Causes unpredictable mood effects and emotional instability: e.g. crying, laughing, panic (bad trip), agitation, day dreaming, & schizophrenia Sympathomimetic effect - hypertension, hyperthermia, tachycardia (rapid heart beat)

84 LSD is not addictive but shows tolerance Tiny amounts of LSD (  g) can produce effects in susceptible individuals – Last 8-12 hrs Doesn’t interact with brain reward systems = not typically ‘addictive’ – Most common pattern is occasional use at weekly or monthly intervals Marked tolerance to behavioral effects – No physical dependence

85 LSD adverse effects Danger is in unpredictability and unreliability of effects and frequency of unpleasant experience (bad trips) Acute negative reactions - ~10% of users – Uncontrollable excitement, confusion, acute paranoia, panic attacks, sensory distortions – Short duration and usually treatable by sedative drugs – Deaths occur by drowning, falling out of windows, walking into path of cars Heavy LSD user – recurrent negative reactions can appear up to a year after last drug use and without further exposure – ‘Flashbacks’ - Usually involve spontaneous return of perceptual distortions, reliving of earlier traumatic experiences – Prolonged reactions can be chronic anxiety or psychoses

86 Marijuana Derived from Cannabis Sativa plants; active ingredient Δ 9 -tetra- hydrocannabinol (THC) Cannabinoid receptors (CB 1 ) are GPCR. – Cannabinoid receptors present in VTA reward pathway – activation increases DA release – CB1 also located in hippocampus – stimulation decreases neuronal activity results in short-term memory loss

87 ACUTE EFFECTS Feeling of well-being, euphoria, laughing, slow harsh speech. Impaired concentration, learning, and perceptual motor skills, disorientation to time and place Visual hallucination, sexual ideation in a dreamy state & panic, disorientation Bulimia particularly for sweets, droopy eyelids, postural hypotension, tachycardia, dry mouth

88 CHRONIC EFFECTS Long-term use leads to cognitive dulling, lethargy, inertia, self- neglect, amnesia, respiratory effects from smoking, compulsive behavior Little tolerance or physical dependence No characteristic (specific) withdrawal syndrome, however, can have general symptoms of irritability, sleeping difficulty, craving, anxiety Addiction – varies. ~10% of general population, higher if start smoking in teen years (~25%)

89 DESIGNER DRUG CANNABINOIDS Large number are flooding market – generally untested in labs At least some are pure agonists at CB1, while natural THC is a partial agonist that does not saturate receptors Some have addictive properties not seen in natural THC

90 Poly-drug intoxication Poly-drug use refers to using 2 or more psychoactive drugs in combination Combination may be intentional to get same effect – E.g. Alcohol plus marijuana for relaxation May have accidental combinatorial effect on same systems in the brain

91 Poly-drug intoxication: example Heath Ledger's death on Jan. 22, 2008 was due to an accidental mixture of prescription drugs, New York City's Chief Medical Examiner has concluded. "Mr. Heath Ledger died as the result of acute intoxication by the combined effects of Oxycodone, Hydrocodone, Diazepam, Temazepam, Alprazolam, and Doxylamine." "We have concluded that the manner of death is accident, resulting from the abuse of prescription medications." Oxycodone is a painkiller, Hydrocodone is also known as Vicodin, Diazepam is commonly called Valium, Temazepam treats anxiety or sleeplessness, Alprazolam is known as Xanax, and Doxylamine is a sedating antihistamine often used as a sleep aid. Dr. Michael Hunter, a prominent forensic pathologist, tells PEOPLE that the combination of the powerful drugs most likely caused "poly-drug intoxication" which led to respiratory arrest. "His breathing probably got slower and slower until it stopped all together," he said.

92 Poly-drug toxicity Poly drug use carries more risk than use of a single drug, due to an increase in side effects and drug synergy. One drug may add or even potentiate another Licit drugs and medicines – such as alcohol, nicotine and antidepressants – can have potentiating effects with controlled psychoactive substances. Fatalities - actions as depressants on respiratory centers

93 Poly-drug toxicity Problematic pharmacological pairings: – alcohol and cocaine increase cardiovascular toxicity – alcohol or depressant drugs, when taken with opioids, lead to an increased risk of overdose – opioids or cocaine taken with ecstasy and amphetamines have additional acute toxicity. – Benzodiazepines can cause death when mixed with other CNS depressants such as opioids, alcohol, or barbiturates

94 Use of mood-altering drugs is widespread Effects of mood-altering drugs have behavioral and social consequences (e.g. addiction) that are beyond typical ‘pharmacological’ effects Nevertheless, pharmacodynamic and pharmacokinetic properties of individual drugs within a drug group strongly affect their influence on individuals

95 THE END