drugs, addiction, and mental disorders

Drugs, Addiction, and Mental Disorders

Gery Schulteis

Professor of Anesthesiology

UC San Diego School of Medicine

Pharmacology

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

“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

Drug Abuse and

Addiction

Definitions

Drug Abuse versus Drug Addiction - Usually drugs are abused first, and addiction comes later

Drug ABUSE (Substance Abuse)*Maladaptive pattern of substance use with significant adverse consequences related to repeated use

Why Are Drugs Used for Nonmedical Purposes?

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

Drugs as ReinforcersReinforcement: Process by which an event or outcome increases the probability of a given response

Positive 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

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 avoidwithdrawal effects

once dependent

Rates of Use and Dependence/Addiction18-54 yr olds

(Relative Addictive Liability)

TobaccoAlcoholIllicit Drugs Cannabis Cocaine Amphetamines Anxiolytics Psychedelics Opioid Narcotics

75.691.5

46.316.215.312.710.6

1.5-10(heroin low, prescription opioids high)

Ever Used24.114.1

4.22.71.71.20.5

0.4-1.5

Prevalence of Addiction

31.915.4

9.116.711.29.24.923.1

Addiction Among Users

From: Anthony JC, Warner LA and Kessler RC, Exp Clin Psychopharmacol, 1994, 2:244-268.

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

Marijuana

Cannabis sativa and related species of flowering hemp plants

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

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)

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

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

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”

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

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



TobaccoAlcoholIllicit Drugs Cannabis Cocaine AmphetaminesPsychedelics Opioid Narcotics

75.691.5

46.316.215.310.6


Ever Used24.114.1

4.22.71.70.5

0.4-1.5


31.915.4

9.116.711.24.923.1



Medical UsesCertain preparations of THC are available for specific clinical uses as schedule II drugs, but marijuana itself is schedule I

1. 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

2. Appetite Stimulation in AIDS patients, chronic cancer patients

3. 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

4. Analgesia (clinical trials currently)

Psychostimulants

• 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

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)

Behavioral Effects

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

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)

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

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

MDMA “Desired” Effects

• Stimulant (reduced fatigue, increased endurance)

• Euphoria• Mild psychedelic effects (less pronounced than

LSD)

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

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

Destruction of Serotonin Neurons by

MDMA

A-C: Frontal CortexD-F: Parietal CortexG-I: Visual Cortex

Normal MDMAAcute

MDMA7 years

Alcohol

Stats120 million drink18 million alcoholics20% binge drinkers

Driving: 40,000 fatalities; 17,500 alcohol related

Cost: $180 billion/year

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

Proof 2x Percent200 proof = 100%100 proof = 50%40% = 80 proof

50% = 100 proof

Beer ~ 4%Wine ~ 10%

Whiskey ~ 40-50%Gin ~ 40-50%

Vodka ~ 40-50%

Legal Blood Alcohol Level0.05 % - Philippines

0.08 % - United States0% - Japan

0.08 grams alcohol in 100ml blood

Time Since Ingestion and Full/Empty Stomach

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)

Toxic EffectsAbuse-Harmful (“Behavioral Toxicity”)

Damage to Self academic impairmentblackoutspersonal injury/deathshort/long-term illnessunintended/unprotected sexual activitysuicideimpaired drivinglegal repercussionsimpaired athletic performance

Damage to Others fights/violencesexual violence, rapehate-related incidentsnoise disturbancesdriving induced injury/death

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)

Normal Healthy Liver

Liver with Cirrhosis

Alcohol & Brain Damage

OpiumPoppy

OpioidNarcotics

DefinitionsOpiate = any drug derived from opium that has

morphine-like effects– Natural: morphine, codeine– Semi-synthetic: heroin, oxycodone (Oxycontin),

hydrocodone (Vicodin)

Opioid = any drug natural or synthetic that has morphine-like effects– Endorphins (the body’s opioids)– Natural– Synthetic



TobaccoAlcoholIllicit Drugs Cannabis Cocaine Amphetamines Anxiolytics Psychedelics Opioid Narcotics

75.691.5

46.316.215.312.710.6


Ever Used24.114.1

4.22.71.71.20.5

0.4-1.5


31.915.4

9.116.711.29.24.923.1



Physiological Effects1. Desired (Medical):

Anti-tussive (cough suppression)

Anti-diarrhea (could also be side-effect (constipation)

2. Undesired (Side Effects):

Nausea

Itching

Constipation

Pupillary Constriction

Respiratory Suppression (the “lethal” one)-overdose

Behavioral Effects

1. Desired Effects:

Euphoria (recreational)

Analgesia (medical)

Sedation/Anesthesia

(medical)

2. Undesired (Side Effects):

Muscle Rigidity

Stereotyped Behavior

Medical UsesDysentery & Severe Diarrhea

– Loperamide (Immodium)– Diphenoxylate (Lomotil)

Analgesia - relieve pain– Chronic pain - cancer– Acute pain - surgery (pre- & post-Op)

Anesthesia - Systemic (IV)- Epidural– Fentanyl (Sublimaze)

Cough– Codeine– Dextromethorphan

Detoxification/Maintenance Therapy– Methadone

Drug dependence – Definition“An adaptive state that manifests itself by intense physical

disturbances when the administration of a drug is suspended…

These disturbances, i.e., the withdrawal or abstinence

syndromes, are made of specific arrays of symptoms and signs

of psychic and physical nature that are characteristic for each

drug type.”

From: Eddy NB, Halbach H, Isbell H and Seevers MH, Bulletin of the World Health Organization, 1965, 32:721-733.

--modern view: “psychic” = negative emotional states of anxiety, depressed mood,

Tolerance and Sensitization• TOLERANCE: a condition of decreased response to a

drug after prior or repeated exposure.

• SENSITIZATION: sometimes referred to as reverse tolerance, is a condition of increased response to a drug after prior or repeated exposure.

Treatment for Addiction

• Detoxification

• Maintenance programs–Methadone clinics (Heroin addiciton)–Slow withdrawal method – aviodance

of the negative consequences of detoxification

• Support Groups–12-step programs (AA,NA, MA)

drugs, addiction, and mental disorders

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