Drugs & Behavior Exam 3

incomplete done through 3/29/24

Alcohol History

• fermentation dev with society

• ethanol → fruit is ripe but not rotten → greater use

• ~1000 BCE China, remedy for diseases

Usquebaugh

Gaelic “water of life”, whiskey derived from, major ingredient of tonics & elixirs

Wood Alcohol

Methyl, synthetic, antifreeze, fuel

Grain Alcohol

Ethyl, fermentation product, drinkable

Rubbing Alcohol

isopropyl, wound disinfection

How to Make Alcohol

1. Fermentation

   1. organic high sugar material + yeast

   2. 1 molecule sugar → 2 molecules alcohol, 2 molecules CO2

2. Distillation

   1. heat fermentation product to vapor then cool, concentrate

Change in Average American Drinking

1800s: 4-5 standard drinks a day

Now: 3-4 standard drinks a day

US Alcohol Use

48.7% 12+ yrs old used in past month

79.7% M and 77.3% F lifetime use

Standard Drink

12 oz beer ~ 8-9 oz malt liquor ~ 5 oz wine ~ 1.5 oz spirits

~30mg/dL alcohol

Alcohol %’s of Common Beverages

Wine - 7-15%
Beer - 4-6%
Liquor - 40-95%

Alcohol Broad Scope

$200 bil/yr, 100,000 deaths/yr, 15.1 mil (1:20) Alcohol Use Disorder, hard to get treatment for, stigma

Alcohol Absorption Types

need LARGE amounts (~14 g standard drink)

Oral most often, other kinds banned in most states

AWOL (inhale, vaportini, alc wo liquid)

Palcohol (powdered)

Alcohol Absorption Molecular Basis

simple small molecule, soluble in water and lipids, neutral

rapidly absorbed (small intestine faster than stomach) into body water (~90% to brain)

food slows down ethanol absorption → lower BAL

Blood Alcohol Level/Concentration (BAL/BAC)

concentration of alcohol in blood

80mg/dL = 0.08g/100mL = 0.08% = 17mM

Metabolic Process of Alcohol

1. alcohol dehydrogenase (redox) : ethanol → acetaldehyde +water

2. Aldehyde dehydrogenase : acetaldehyde → acetate, NADH out

   1. alcohol levels below 0.1g/dL (22mM)

3. Else- Microsomal Ethanol Oxidizing system : ethanol → acetaldehyde

   1. NADPH → NADP+, cytochrome P450

   2. byproducts: toxins, free radicals, H2O2

4. Acetate → water & CO2 or acetyl-CoA

Disulfiram

antabuse, blocks aldehyde dehydrogenase, increases hangover effects from acetaldehyde

negative reinforcement, people avoid taking (attrition)

Alcohol & the Liver

fatty acid buildup leads to cell death, alcoholic hepatitis → cirrhosis → liver failure

SOME alcohol breakdown in the stomach (more for males)

Alcohol Excretion

unchanged through lungs (~2-8%, breathalyzers)

90-95% slowly oxidized through the kidneys

increased urination, suppresses antidiuretic hormone

Alcohol Pharmodynamics

• Nonspecific: disturbs P-membrane, polar phospholipid head, alters lipid comp

• Specific: acts as NT at binding site, mods channel gating mech, channel P change, stim Gs-adenylyl cyclase

  • dirty drug. many assorted effects. GABA- DA, opioid peptides, glutamate input

Alcohol Mechanism of Action

increases GABA(A), up inhibition, decreases glutamate, alters function of many proteins at once

acts on ligand-gated ion channels (nicotinic actylcholine, 5-HT3), metabotropic (da and opioid), and voltage gated ion channels (Ca2+, Na+)

Alcohol Behavioral effects

• BAC (g/dL): 0.05-0.1 (11-22mM) : subjective high “buzz”, anxiolysis, sedation 

• 0.1-0.2 g/dL (22-44mM) : motor impairment, slurred speech, blackout 

• 0.2-0.3 (44-66 mM) : emesis (vomiting), stupor (near unconsciousness)

• 0.3-0.4 (44-99 mM) : coma 

• >0.5 (110mM) : respiratory depression, death

• takes more alcohol to kill chronic users

Alcohol Peripheral Effects

• dilates blood vessels, dec body temp

• increases other depressant drug effects

• perception change

Alcohol Tolerance & Withdrawal

acute (one sitting), chronic, and metabolic

sleep disruption, ANS (sympathetic NS) activation, tremors, seizures, psychological dependence

~10-15% use at detrimental levels

Alcohol Reinforcing Effects

Positive: slow (PK), pleasure, altered consciousness, peer conformance

Negative: relief of stress, negative emotions, pain, and withdrawal symptoms

damage PFC → compromised decision making, emotional effect, and executive function

Korsakoff Syndrome

brain damage from alcohol, leading cause of dementia, loss of white and gray matter → brain shrinks!!!

greater risk for older people and the frontal lobes

Negative Alcohol Effects

• J shaped cardiovascular - helps (10-40% reduced risk) then worsens in higher amts

• coronary heart diseases (sat fat & cholesterol), arrhythmias, cardiomyopathy hemorrhagic stroke

• hypertension, esophagus reflux or cancer, stomach gastritis, pancreas inflammation and pain

  • intestine chronic diarrhea, malabsorption

Naltrexone

Revia, opioid antagonist, ant-alcohol treatment, reduces craving

blocks reinforcing effects, reduces relapse, works better with behavioral therapy combo

Acamprosate

may block NMDA receptors, alcohol pharmacotherapy

Behavioral Alcohol Treatment

• alcoholics anonymous - 26-50% success rate after 1 yr, abstinence, self recognized helplessness

• behavioral therapy - controlled drinking, mod/control amt and frequency ingested

• adverse therapy - pair alcohol with unpleasant consequences (psychosocial)

Papaver somniferm

opium plant, frost tolerant annuals, sleep related

found in the middle east/mediterranean sea and cultivated in Asia

Opium Extraction

• petals off to egg sized seedpod

• lightly score seedpod and collect white sap (opium)

• dry the sap → thick & gummy can be smoked or ingested

Opium History of Use

• 6000 yrs ago Sumerian s and Assyrians

• 3500 yrs ago Egypt (Therapeutic Papyrus of Thebes)

• ~150 CE greeks and romans pancea (Galen)

• widespread use in Islamic cultures and china

• 19th cent → western use

Morphine

F.W. Serturner id as active component

10x as potent as opium

hypodermic syringe, 1800s, civil war’s soldier’s disease

Opium Derivatives Potency

opium < morphine(x10) < heroin(x2) < fentanyl

Diacetylmorphine (heroin)

Alder Wright, cough suppressant and pain killer, 1874

Harrison Narcotic Act (1914)

beginning of US drug crime, up prices

addendums of prescribe only with reducing doses, no prescription to addicts, and never prescribing heroin

Prescription Opiates

Poppy (opium, morphine)

• Codeine, dilaudid (semi-synth), 

• oxycodone/oxycontin (semi-synth)

• Percodan (aspirin + oxycodone)

• Percocet (acetaminophen + oxycodone)

• Vicodin (acetaminophen + hydrocodone)

Synthetic Opiates

higher rates of OD deaths

oxycontin (extended release ~12hrs but people crush & snort & die.)

fentanyl (SEVERE pain, actiq, duragesic, sublimaze, high potency, reduces therapeutic window, more sedative)

Opium Absorption

oral - gastronintestinal

injected - intravenous quicker (mainlining)

‘smoked’ (inhaled) - through nasal mucosa & lungs

Opium Distribution/Metabolism/Excretion

• morphine - small amt cross BBB

• heroin - more lipid soluble, prodrug, converted to morphine in brain

• liver metab ~2 hrs, some to normorphine

• codeine → morphine

• kidneys/urine eliminate, sex/age/diet/genetics/disease states/meds influence

Opioid Neurotransmitters

• Naloxone (1960s, sim to morphine)

  • blocks effects, reverse overdoses

  • antagonist, narcan

• Endorphins (endogenous morphine, 70s)

  • Pert & Snyder, NT opiates mimic

  • beta- , enkephalin, dynorphin

Endorphins

brain’s natural pain-relief. released from injury

acupuncture and placebos release

naloxone blocks

Opiates Brain Effects

• mimic endorphins (endogenous opioid peptides)

• agonist

• directly effect activity, uses intrinsic pain-modulating circuitry, additional therapeutic effects

Opioid Systems of Effect

• sensory - pain inhibition

• modulatory - gastrointestinal, endocrine, autonomic

• emotional - rewarding & addicting

• cognitive - mods learning and memory

Mu μ Opioid Receptor

endorphin, agonist

analgesia (supraspinal), euphoria, down GIT, miosis, respiratory depression, physical dependence

Delta δ Opioid Receptor

enkephalin, agonist, analgesia (spinal & supraspinal), growth hormone, affective behavior, limbic system

Kappa κ Opioid Receptor

dynorphin, agonist, analgesia (spinal), sedation, miosis

Opioid Receptors Overall

metabotropic (g-protein coupled), agonist, inhibit neurons, activate K+, inhibit Ca2+ & neurotransmitter release

Opioid Pharmacological Effects

euphoria, analgesia, drowsiness, reduced anxiety, ‘heavy’ limbs, respiration depression, cough suppression, miosis (pupillary constriction), nausea, vomiting, impotence, loss of desire, vivid dreams

Opiate Pain Signalling

GABA-ergic, pain inhibitory

Opiates on Reward System

Opiate Tolerance And WIthdrawal

decreased receptors, increased liver enzymes, conditioned tolerance

depression, crying, high anxiety, irritability, panting, diarrhea, pos → neg reinforcement, flu like symptoms ~6-12hrs after last dose

HIGH relapse, environmental and pavlovian (‘nam vets 21% addiction rate, few relapses at home)

Opiates Medical Use

• pain without unconscious (heroin schedule I)

• end stage cancer (w low dose Naltrexone)

• diarrhea, cough (dextromethorphan)

• opioid use disorder

Opioid Lethality

no organ damage

OD deaths. small LD/ED ratio. unstable tolerance

toxic substances combined with, mixing (speedball - heroin & cocaine)

Opioid Replacement Therapy

• Methadone - maintain, harm reduction, individualized, up abstinence down crime, HIV, death

• Naloxone (narcan) - reverse effects, pops opioid off receptor antagonist, full affinity

• Buprenorphine (suboxone) - best of both, partial agonist / antagonist

Cannabis Sativa

“intoxicant”, marijuana leaf, hashish = dust/resin for plant protection

Marijuana Historical Use

• stone age pots

• Shen Nung for medicinal (sedation, analgesia, psychoactive)

• India religious use

• ME and North Africa speed up child birth

• ~1800s Western, medical & mental illness (Moreau)

Marijuana Regulation

Marijuana Tax Act 1937 - criminalization, weed → harmful actions

LaGuardia Committee Report 1944 → multidisciplinary, weed not harmful, no aggression with. mental confusion, delirium, excitation, and anxiety noted

US National Academy of Science → treatment for pain, nausea, and vomiting

Marijuana Use

most widely used elicit drug in the western world

3rd most common (alcohol first nicotine second)

~3-4% worldwide, inverse to perceived risk

Marijuana Absoption

chew leaves or smoke

joint = cig, blunt = emptied out cigar, vapor = vape/pipes/bong

peak ~30 minutes, lasts 2-4 hours

potency, ~20% active ingredient absorbed

Marijuana Distribution & Metabolism & Elimination

highly lipid soluble, into fatty tissues. detectable when blood lvl = 0

liver & organs → less active compounds

feces/urine (half life 1 week), detectable up to 30 days later (single use)

Marijuana Structure

more than 60 compounds

delta-9-tetrahydrocannabinol (THC) = psychoactive component

Marijuana Potency

• highest sinsemilla (seedless) - 10-30% THC

• lower US - from ~2% → 8-10%

• hash oil → ~20%, max ~60%

Marijuana Pharmacodynamics

CB1 (CNS) and CB2 (PNS/immune system)

metabotropic, natural receptors

postsynaptic synthesis, presynaptic receptors (retrograde)

inhibit release of glutamate, GABA, noradrenaline, dopamine, 5-HT

Endocannabinoids

endogenous, Anandamide (bliss) and 2-arachidonoyl-glycerol (2-AG)

Marijuana Effects

acute - differ per user, benign, thirst, down motor & REM, up talking and hunger, nausea/headache

cardiovascular - red eyes (conjuctiva), vasidilation (after 1 hr), dose dependent

Some reactions learned, experienced more sensitive

Learning Effects on Marijuana

1. Mechanical - inhalation & increased absorption

2. Perceptual - perceive physical and psychological effects

3. Labeling - label pleasant effects

Marijuana Behavioral Effects

decreased psychomotor, relaxed/tranquil. keener perception, down sensitivity to pain, varied effect on sexual function (but long term to impotent or disinterest)

Marijuana Cognitive Effects

impaired short term memory (in encoding, consolidation, and information retrieval. greater for teens)

reduced neurotransmission - impaired long term potentiation (inc synapse strength) and long term depression (decrease synapse strength)

lengthened sense of time (decreased)

down critical thinking, judgement, and attention/vigilance

Marijuana Emotional Effects

carefree, relaxed, euphoric, content, excited

~1/3rd → anxiety, dysphoria, suspicion, paranoia

inconclusive links to schizophrenia/psychosis, depression, and anxiety

Marijuana Physiological Effects

up hr and bp (after 20mins last 1hr)

decreased proper lung function (reversible?)

weed cigs have more tar and carcinogens, hold smoke in longer, varied results per symptom of worse

emphysema, no long term cardiovascular effects, some immunosuppressant but nothing long term

reduced sperm count/motility, non-ovulatory menstrual cycles

Marijuana Addictive

activates reward pathway, tolerance in animal

withdrawal - sleep disturb, nausea, restless with heavy use

neuroadaptations. yes addictive.

Amotivational Syndrome

controversial theory that weed → unmotivated and lazy

likely from pre-existing personality characteristics

Marijuana Gateway Drug?

no. stepping stone like: ethanol/nicotine → marijuana → hard drugs.

90% cocaine users done weed not converse

correlative vulnerability - general predisposition to use drugs

Cannabis Medical Uses

schedule I drug (no med use). historically used

reduces vomiting and stimulates appetite, for cancer

cachexia (stim appetite), pain, epilepsy, hypertension, asthma, anxiety, alzheimer’s, depression

glucoma (reduce eye pressure, side effects)

Synthetic Cannabinoids

schedule III (med use allowed)

more specified, only target one receptor type, fewer side effects, more potent, stable, and soluble. slow

marinol (dronabinol), cesamet (nabilone), sativex (oral spray → pain killer sclerosis arthritis)

rimonabant (inverse agonist, obesity, alzheimers)

CBD

cannabidiol

self admin, little reinforcement, psychoactive side effects

Hallucinogens

change mental state by distorting perception of reality

illusionogenic, psychotomimetic, psychedelic, mind expanding

Serotonergic Hallucinogens

LSD (lysergic acid diethylamide), mescaline (peyote cactus), psilocybin, lysergic acid amide (morning glory seeds), DMT (dimethyltryptamine),

change serotonin transmission

Hallucinogens History

religious ceremonies, shrooms before 1000 bce, rituals in Mexico

Switzerland Hoffman, 1938, derivative of fungus ergot, for psychotherapy

60s: western culture, ~2 mil tried LSD in the US, claims of health risks (insanity, suicide, violence)

Methylated Amphetamines

MDA, MDMA (ecstasy)

Anticholinergic Hallucinogens

mandrake, henbane, belladonna, jimsonweed

Dissociative Anesthetics

angel dust, ketamine

LSD

potent, 50-150 microgram street dose, effective dose 10 micrograms

similar structure to serotonin

Serotonin

regulation of sleep, mood, impulsivity, cognition

blood, brain, GI tract, 7 receptor classes, 14 subtypes

produced in the raphe nucleus → central nervous system

analgesia, sleepiness, change in appetite

most metabotropic, some ionotropic, hormonal messenger traits

LSD Mechanism of Action

serotonin receptor partial agonist

mimics serotonin, alters system

higher affinity for 5HT2A, cross tolerance

Mescaline Mech of Action

psychoactive compound in peyote cactus

different structure, acts on 5-HT receptors

cross tolerance

Serotonin Hallucinogens

• LSD most potent - ~20 min, lasts 8-12hrs

• Morning glory seeds (lysergic acid amide) - ~10% LSD potency

• Psilocybin - variable, ~1% LSD

• Mescaline - ~10-14 hour trip, ~1/3000 LSD

• DMT (dimethyltryptamine) - plant used to make tea, least potent, ~1 min kick in, ~1 hr trip

Hallucinogen Psychotherapeutic Use

Past- produce model psychosis, induce hallucinogens, destroy ego defenses, visual (drugs) vs auditory (schizo). risks outweighed benefits

Hallucinogen Effects

sim to stimulants, sympathomimetic (up HR and BP and body temp, pupil dilation)

visual, vivid, dream like hallucinations, synthesia, labile mood (magical thinking, cosmic sig)

altered cognitive experiences

Hallucinogen Side Effects

bad trips - acute paranoia, psychotic state

flashbacks (months/years later)

psychiatric disorders - manson family/cult, prepsychotic symptoms

Hallucinogens Tolerance

cross btwn hallucinogens

LSD hallucinogens and physical within days of use

days of abstinence to return of effect; days to complete tolerance

MDMA

ecstasy, club drug, high use in the 90s

schedule I ‘85

Methylated Amphetamines

• intake: oral, inject, snort

• effect last 6-8 hours

• MDMA 75-150 mg, MDA 50-150 mg

Methylated Amphetamines Pharmacodynamics

blocks serotonin transporters (reuptake), and a bit of dopamine. Increase monoamine release

sympathomimetic, like stimulants

followed by a low

Methylated Amphetamines Physical Effects

• Suppressed appetite, elevated heart rate 

• Increased blood pressure and body temp

• Sweating and salivation, insomnia 

• Muscle tension 

• Bruxism (teeth grinding), trismus (lockjaw)

Methylated Amphetamines Psychological Effects

• Euphoria, up emotional warmth and empathy, up talking

• Down defensiveness, hallucinations are NOT common 

• Effects from drug AND environment 

Methylated Amphetamine Withdrawal

Drowsiness, muscle pain, depression, paranoia, anxiety

Methylated Amphetamine Toxicity

• Dehydration, heatstroke, heat exhaustion, muscle breakdown, kidney failure, stroke, seizure, heart attack - sympathomimetic effects 

• combo effects (envi too) - adulteration from more

• after mult. high doses, synergistic effects with other drugs

Methylated Amphetamine Long Term Effects

Depletion of 5-HT and/or loss of 5-HT nerve terminals

(after single high dose or multiple low doses)

depression and cognitive deficits ??