Understanding Drugs, Addiction, and Mental Disorders

1. Drugs, Addiction, and Mental Disorders Gery Schulteis Professor of Anesthesiology UC San Diego School of Medicine

2. Pharmacology

3. Definitions • Pharmacology • From the Greek “pharmacon” (drug, medicine, or poison) and “logia” (study of)--the study of the interaction of drugs with living materials • Neuropharmacology • Study of drugs affecting the nervous system

4. “Drug” Defined • General Definition: any chemical agent other than food that affects a living organism • Ingredients in some foods (e.g. caffeine in chocolate) can be considered drugs • Drugs can correct imbalances in chemical systems, giving them therapeutic potential • Psychoactive drugs are drugs that act on the central nervous system to affect behavior

5. Drug Abuse and Addiction

6. Drug Abuse versus Drug Addiction - Usually drugs are abused first, and addiction comes laterDrug ABUSE (Substance Abuse)*Maladaptive pattern of substance use with significant adverse consequences related to repeated use Definitions

7. 1. Positive feelings - pleasure (positive reinforcement)2. Mask psychological distress, self-medication (negative reinforcement)3. To be more social4. To gain attention and/or acceptance5. Express emotions6. Search for meaning and independence7. Rebellion8. Enhance creativity9. Experience risk10. Alleviate curiosity/boredom Why Are Drugs Used for Nonmedical Purposes?

8. Reinforcement: Process by which an event or outcome increases the probability of a given responsePositive reinforcement: PRESENTATION of an outcome increases the probability of a response(outcome = drug “high”, response = seek more)Negative reinforcement: TERMINATION of an event increases the probability of a response(event = anxiety, drug intake terminates anxiety, response = seek more) Drugs as Reinforcers

9. Positive Reinforcement • Examples: • Work hard and get praise from • your boss • A child cleans his room to get • candy • Drink alcohol to feel good • and be more outgoing • Negative Reinforcement • Examples: • Work hard to avoid getting laid • off • A child cleans his room to avoid • a spanking • Drink alcohol to avoid severe • anxiety, or to avoid • withdrawal effects • once dependent Drugs as Reinforcers

10. Prevalence of Addiction Addiction Among Users Ever Used Rates of Use and Dependence/Addiction18-54 yr olds(Relative Addictive Liability) Tobacco Alcohol Illicit Drugs Cannabis Cocaine Amphetamines Anxiolytics Psychedelics Opioid Narcotics 75.6 91.5 46.3 16.2 15.3 12.7 10.6 1.5-10 (heroin low, prescription opioids high) 24.1 14.1 4.2 2.7 1.7 1.2 0.5 0.4-1.5 31.9 15.4 9.1 16.7 11.2 9.2 4.9 23.1 From: Anthony JC, Warner LA and Kessler RC, Exp Clin Psychopharmacol, 1994, 2:244-268.

11. Age of Onset of Use as a Factor in Lifetime Addiction Risk

12. Marijuana

13. Cannabis sativa and related species of flowering hemp plants

14. THC • Very lipophilic (likes to be surrounded by fats), so THC and its metabolites can accumulate in fat deposits and are cleared from the body slowly as a result • Blood levels of THC can be detected for 6 days • Urinary metabolites can be detected for up to 6 weeks

15. Behavior • Euphoria: pleasure, feeling “high” (mild) • Perceptual Changes • Motor Performance Declines • Mental Performance Declines • Decreased Motivation • Panic reactions/psychosis • Psychotomimetic (mimic symptoms of psychosis/schizophrenia) • Increase in appetite (munchies)

16. Perceptual Changes • Psychedelic • Mind clearing • Mind expanding • Hallucinogen • Seeing/hearing something that is not there • Drugs do not generally do this, but they distort/ enhance what is there, so psychedelic a better term

17. THC Perceptual Changes • COMMON: • Time perception is slowed • Distortions of space with near objects appearing distant • LESS COMMON but POSSIBLE: • Visual “hallucinations”- flashes of light, amorphous forms of vivid color, depth of color increased • Auditory- sounds magnified, keener appreciation of rhythm and timing • Synesthesia - transmutation of senses • Seeing sounds • Hearing colors

19. Mental Performance • Impaired judgment, impaired memory and confusion • Impaired free recall memory of material learned while intoxicated • Deterioration in capacity to perform tasks requiring a sequence of mental steps- “temporal disintegration”

20. Amotivational Syndrome • Lack of motivation, direction, ambition • Poor school performance • Personality deterioration • General decrease in function • Inability to hold a coherent conversation • Chronic intoxication • More likely to occur in high-dose compulsive users • Often remits with cessation of use

21. Panic Reactions- Psychosis • Marijuana use can lead to panic-like reactions • Acute psychotic episodes characterized by delusions and loosening of associations observed in some individuals • Short-term exacerbation or recurrence of pre-existing psychotic symptoms • Precipitate a schizophrenic-like psychosis

22. Prevalence of Addiction Addiction Among Users Ever Used Rates of Use and Dependence/Addiction18-54 yr olds(Relative Addictive Liability) Tobacco Alcohol Illicit Drugs Cannabis Cocaine Amphetamines Psychedelics Opioid Narcotics 75.6 91.5 46.3 16.2 15.3 10.6 1.5-10 (heroin low, prescription opioids high) 24.1 14.1 4.2 2.7 1.7 0.5 0.4-1.5 31.9 15.4 9.1 16.7 11.2 4.9 23.1 From: Anthony JC, Warner LA and Kessler RC, Exp Clin Psychopharmacol, 1994, 2:244-268.

23. Medical Uses Certain preparations of THC are available for specific clinical uses as schedule II drugs, but marijuana itself is schedule I • Anti-emetic Agent • Marinol, Nabilone (THC) or Cesamet (a synthetic THC analog) given to chemotherapy patients for controlling nausea and vomiting • Have added benefit of stimulating appetite and producing elevated mood and analgesic effects, albeit mild • Appetite Stimulation in AIDS patients, chronic cancer patients • Treatment of Glaucoma (not FDA approved yet, but patients smoke) • Leading cause of blindness due to buildup of excess pressure of fluids in the eyeball • Analgesia (clinical trials currently)

24. Psychostimulants

25. Cocaine (Erythroxylum coca derivative) • Cocaine HCl (snorted, injected) • Free Base (smoked) • Crack (crystalline free-base) • Amphetamines (first synthesized in 1887) • D-Amphetamine (Dexedrine + more…) • Oral, Injected • Methamphetamine (Desoxyn, Methadrine) • Oral, smoked (“Ice”, “Meth”. “Crystal”, “Shabu”) • Methylphenidate (Ritalin) • Phenmetrazine (Preludin) • Methylphenidate (Ritalin) • d and l Amphetamine (Adderal) • Oral

27. Physiological Effects • Autonomic Nervous System Activation (Sympathetic Reaction, Fight/Flight Response): • --sympathetic system prepares body for action • Increased heart rate • Increased blood pressure • Increased body temperature (hyperthermia) • Dilated bronchial passages (airway)

28. Behavioral Effects • Euphoria (feeling of pleasure, wellness) • Improves performance (under conditions of fatigue) • Alleviates fatigue • Decreases appetite (anorexic) • Increases violent tendencies

29. Medical Uses • Amphetamines • Historical: • Bronchial dilator (asthma treatment), popular in 1920’s • Appetite suppressant, big in 1950’s • Depression • No longer prescribed much for these purposes given high abuse liability, “safer” drugs available for these purposes • Current: • Narcolepsy • Attention Deficit Disorder • Still among best options for these disorders • Orally, often sustained release to limit “high” and abuse liability (related to rate of drug entry into brain) • Over-the-Counter (e.g. pseudoephedrine, ephedrine) • Related compounds with limited Central Nervous System actions used in cold/flu/asthma/allergy medications • Decongestants, bronchial dilation, etc. • Peripheral Actions on Autonomic Nervous System • Certain preparations limited in how much one can buy now • (cooking meth from related molecules)

30. Medical Uses • Cocaine HCl • Local Anesthetic • Property not shared by amphetamines • Cocaine structurally similar to other locals such as lidocaine, procaine, novocaine, etc. • 1-4% solutions • Only for certain painful exams of upper digestive and respiratory tracts (laryngoscopy, bronchioscopy, etc.) • Combines local anesthetic action with constriction of local blood vessels to reduce both pain and risk of bleeding • Mechanism of Local Anesthetic Action Unrelated to Stimulant Properties, not shared by amphetamines

31. MDMA (Ecstasy) • First synthesized in 1912 as a potential appetite suppressant, never marketed due to “psychedelic” properties • Repopularized as a drug of abuse in early 1980’s as part of the designer-drug craze (modify illegal molecules like methamphetamine to make them legal) • Potent psychostimulant, has most effects of cocaine and amphetamines, but added pyschedelic effects due to action on neurotransmitter system that cocaine and amphetamines do not affect much

32. MDMA “Desired” Effects • Stimulant (reduced fatigue, increased endurance) • Euphoria • Mild psychedelic effects (less pronounced than LSD)

33. MDMA Acute Side Effects • Stereotyped Behaviors (jaw clenching, tooth grinding, restless limb movements) • Increased Body Temperature • In combination with excess activity at dance parties, can lead to dangerous levels of hyperthermia/heat stroke • Sympathetic Activation (increased HR, BP) • Again potentially dangerous in combination with excess activity • Drug-Induced Psychosis

34. MDMA Acute Overdose: Sympathetic Stimulation and Excessive Activity Cardiovascular Toxicity: • High blood pressure via sympathetic effects combined with excessive exercise can lead to ruptured blood vessels (stroke if in brain, myocardial infarct if vessels supplying blood to heart) • Cerebral Toxicity/seizures: • Sympathetic effects in combination with excess activity can promote excessive fluid loss from sweating • Many drink lots of water to avoid this • Water replaces fluid, but not electrolytes • Hemodilution results in osmotic imbalance, water leaves bloodstream, enters tissues • When tissues are brain tissues, seizures can result from excess pressure/swelling • Sometimes the brainstem and cerebellum can be pressed down towards the narrow opening in skull cavity where spinal cord enters, can cause disruption of centers regulating respiration, HR (death) • Hyperpyrexic Toxicity: • Basically heat-stroke, in severe form malignant hyperthermia • Damage to many tissues/organs, including muscles, kidneys (renal failure possible), liver

35. MDMA 7 years MDMA Acute Normal Destruction of Serotonin Neurons by MDMA A-C: Frontal Cortex D-F: Parietal Cortex G-I: Visual Cortex

36. Alcohol

37. Stats 120 million drink 18 million alcoholics 20% binge drinkers Driving: 40,000 fatalities; 17,500 alcohol related Cost: $180 billion/year

38. Alcohol • Ethanol • Drinking alcohol • Many other types, but most are very toxic if consumed • E.g. methanol--metabolized to formaldehyde • Oral route is primary route of administration for humans • Absorption: 10% in stomach, 90% small intestine

39. Proof 2x Percent 200 proof = 100% 100 proof = 50% 40% = 80 proof 50% = 100 proof Beer ~ 4% Wine ~ 10% Whiskey ~ 40-50% Gin ~ 40-50% Vodka ~ 40-50%

40. Legal Blood Alcohol Level 0.05 % - Philippines 0.08 % - United States 0% - Japan 0.08 grams alcohol in 100ml blood

41. Time Since Ingestion and Full/Empty Stomach

43. Alcohol-Physiological Effects • Vasodilation (widening) in peripheral vessels (skin); causes decrease in blood pressure • Increased sweating • Increased urine production (diuresis) • Body temperature decreases • Low doses: sweating may dissipate some heat • High doses: direct suppression of central thermoregulation centers in brain, dangerous levels of hypothermia • Nausea and vomiting (the body trying to save us from our stupidity)

44. Toxic Effects Abuse-Harmful (“Behavioral Toxicity”) Damage to Self academic impairment blackouts personal injury/death short/long-term illness unintended/unprotected sexual activity suicide impaired driving legal repercussions impaired athletic performance Damage to Others fights/violence sexual violence, rape hate-related incidents noise disturbances driving induced injury/death

45. Toxic Effects of Alcohol • Cirrhosis of the body • Liver • Heart • Pancreas • Cirrhosis of the brain • Wernicke’s/Korsakoff’s Syndrome • Fetal Alcohol Syndrome • Potentially Life-threatening withdrawal (seizures, cardiovascular collapse) • Most will drink long before getting to this point to avoid onset of anxiety and depressed mood, which may be seen before BAL even drops to “0” • Severe withdrawal must be managed medically (other sedative drugs substituted for alcohol and slowly titrated down to nothing)

46. Normal Healthy Liver Liver with Cirrhosis

47. Alcohol & Brain Damage

50. Opioid Narcotics OpiumPoppy