Flashcards: 3. addiction and substance abuse

it affects:

healthcare costs

lost productivity costs

criminal justice costs

other direct costs

trend is on the rise

alcohol

heroin

crack cocaine

mushrooms

buprenorphine

LSD

using a drug in a fashion inconsistent w/medical or social norms

cluster of cognitive, behavioural, physiological Sx indicating that the person continues using the substance despite significant substance-related problems

it depends on psychosocial, economical, health and cultural contexts

some cultures moderate alcohol consumption is normal (western vs muslim)

psychedelics used to not be considered drug of abuse until 60s but now are being researched

debated opinions on alcohol, nicotine, cannabis

given dose produces smaller response then when initially taken -> develops over regular/chronic use of drug

decreased drug response from repeated doses

tolerance to one drug produces tolerance to other similar drug -> tolerance to 1 opioid = all opioids

abstinence/withdrawal Sx if drug is discontinued -> body adaptation to long term physiological drug effects

intense motivational cravings to consume drug

ability of a drug to support dependence to another drug -> methadone alleviates Sx of fentanyl withdrawal

Sx associated w/drug discontinuation when dependent -> usually opposite of the drug effects

long term receptor regulation (body is less sensitive)

an increase in minimum effective concentration

rightward shift of dose-response curve

may decrease max efficacy

special short term dynamic tolerance

basically a "lag phase"

altered (increase or decrease) drug metabolism (increased clearance of drug or reduced uptake)

usually decrease duration of response

special short term kinetic tolerance

the opposite of drug effects

basically your body gets used to the drug being there, makes a new homeostasis with the drug present, so when drug leaves your body is freaking out

using DSM-5 -> need at least 3 of criteria, 4-5 is moderate SUD, 6 or more is severe SUD

look at slides to know the criteria

ventral tegmental area (VTA) -> DA production area

Da travels to amygdala (emotions to physiological response), hippocampus (short term memory), nucleus accumbent (regulating behaviours) and prefrontal cortex

there's also glutamine and gaba neurotransmitters circulating between these areas

VTA is the driver -> promotes behaviour

pre frontal cortex -> inhibitor, controls impulsion

dysregulation

repeated substance use -> neurobiological changes (I.e. DA release) -> behaviour is reinforced

the VTA has more control and prefrontal cortex has less control

binge/intoxication: dorsal striatum, VTA, cerebellum -> withdrawal/negative affect: BLA, CeA (fear response) -> preoccupation/anticipation : PFC, hippocampus (worried, anticipating bad Sx of withdrawal)

becomes more and more about avoiding withdrawal

food or drug always available -> direct comparison

increasing workload to get dose -> measures addictive power

addiction isn't as much mental as It is physical

all these rats were put in a park with a bunch of other rats and drugs -> never became addicted

even rats who were addicted prior recovered

usually gradual addiction

curiosity exposure -> occasional usage -> compulsive usage

reinforcing properties: good feelings/pleasurable experiences

withdrawal avoidance: depends on dose/abuse period, greater if large dose for long period

drug availability

social factors: negative (peer pressure) + positive (social), explains 1st exposure and continuing use despite side effects

psychological craving: intense subjective need for drug, most important for relapse

individual variability: impulsive behaviours, mental illness, genetics

1- any decrease in consumption

2- associated gains in health, functioning, QoL

- complete cessation is a faraway goal achieved via incremental improvements

- expect relapses

- w/proper therapy benefits for 50% of patients

therapy to address drug-associated emotional distress

- funeral ceremony -> go through stages if grief

substitute rewarding effect of drug w/another reward

- fulfill the DA surge w/healthier alternative -> social break vs smoking break

set external incentives/nudges to discourage drug use

- re-organize the routine -> buy morning newspaper at new dep

pharmacological agents to modify effects of abused drugs

- decreased euphoria or cravings -> disulfiram, e-cigarettes

20% in stomach 80% in duodenum -> reaches duodenum faster if you didn't eat

gastric emptying = major determinant -> full stomach is busy dealing with food so it is absorbed slower

non polar -> easily crosses BBB

water soluble -> higher effects on females (higher percent of body fat + lower body weight

ethanol -> (ADH) -> acetaldehyde -> acetate -> into circulation

secondary pathway : ethanol -> CYP2E1 -> acetaldehyde

- CYP2E1 expression is increased in chronic use, why people need more alcohol to feel drunk

hypoactive ALDH -> buildup

zero order kinetics:

average elimination rate = 1 drink/hour

easy to drink faster than its elimination

therapeutic index = 4 (very very low)

dose dependent CNS depression via GABA (inhibition) potentiation + glutamate (excitatory) inhibition -> high affinity for GABA receptor

reward pathway activation via 5-HT (removes inhibition) receptor activation -> increased dopamine + endorphins release from the VTA (why it acts like stimulant

0.05% -> increased confidence euphoria: frontal lobe

0.08 -> legal driving limit

0.10 -> altered judgement: frontal lobe

0.15 -> tremors, ataxia, reduced attention -> parietal

0.20-> reduced motor skills, slurred speech -> parietal

0.25-> altered perception: occipital

0.30-> altered equilibrium, double vision: cerebellum

0.35->apathy: diencephalon

0.40-> stupor, coma: diencephalon

0.45-> resp depression (most common cause of alcohol overdose): medulla

remember it is a CNS depressant

CNS: • Vomiting • ComaRespiratory: • Respiratory Depression

Cardiovascular: severe hypotension -> renal failure + cardiogenic shock

Caution:

• Cannot correct hypotension with vasoconstrictors (not about diameter it is about contraction of heart + stroke volume)• Do not give stimulants to compensate - masks Sx

Tolerance develops to all effects EXCEPT Respiratory Depression

• Cross-Tolerance with Barbiturates & Benzos (also acts on GABA) / NOT Opioids (does not act on GABA)

Intensity proportional to dose & duration of abuse

• Potentially fatal withdrawal rebound CNS excitation -> excessive communication + neural stimulation + APs = influx of Ca2+ -> rigger of apoptosis + cell death -> lots of neuronal death

14+ drinks for males

7+ drinks for females

also look at DSM-5 criteria

risk of AUD

• Potentially fatal due to cardiovascular collapse• Lasts ≈ 5-7 days (increasing severity)• Symptoms: Vomiting / Hallucinations / Intense Tremors / Seizures

• Major cause of car crash & industrial accidents • Psychological dysfunctions / Malnutrition / Other harmful effects discussed earlier

Benzodiazepine = Best option

Very safeStabilizes vital signs ↓ Sx intensity↓ risk of seizures &

hallucinations

can also use beta blockers, alpha agonists, anti epileptic

Naltrexone (opioid antagonist)

• Most effective• ↓ Reward effect & cravings

Disulfiram -> inhibits ALDH -> increases acetaldehyde -> increases negative effects

• Moderate efficacy

• Avoid any alcohol (sauces, lotions, etc.)

12 oz beer

12 oz cooler

5oz wine

1.5oz spirits

0 drinks = no risk

1-2 = low risk

3-6 = moderate risk, cancer risk increase

>7 = high risk

• Pregnancy: No known safe amount of alcohol use

• Breastfeeding: Not drinking alcohol is safest

Males: Far more injuries, violence and deaths

Females: Above the moderate risk zone, health risks increase more steeply

• Moderate drinkers have ↑ lifespan• Correlation ≠ Causation

• Conclusion: Few drinks now and then can be ok but don’t start just for that!

studies have consistently proposed cardiovascular benefits associated with light alcohol consumption.

hepatotoxicity

major cause of fatal cirrhosis (permanent damage)

look at drawing in slide of MoA

alcohol is carcinogen that can cause at least 7 types of cancer

fetal alcohol syndrome

If drank before realising you were pregnant no need to panic.

The absolute risk remains low with low exposure.

Stress/Anxiety is even worse on the fetus!!

Alcohol also concentrates in breastmilk

Lowest-risk timing = WHILE you are breastfeeding

By the time the alcohol reaches the milk, the feeding will be over and there will be a longer time gap until the next feeding to eliminate the alcohol.

drinking a little alcohol neither decreases/increases risk of heart disease, but is risk factor for most other types of cardiovascular disease (hypertension, heart failure, stroke)

Gastritis & Pancreatitis

Hypoglycemic Effect

↓ Gluconeogenesis + Impaired Glycemia Feedback

Pro-Osteoporosis Effect

↓ Growth Hormone↓ Bone Deposition & ↑ Resorption

↑ Snoring & Sleep Apnea

CNS Depressants: Additive Effects

Ex.: Benzodiazepines / Opioids ↑ Respiratory depression

Antihypertensive Rx

Low alcohol ↓ BP vs. High alcohol ↑↑ BP

NSAIDs: ↑ Gastric Bleeding

Peptic Ulcers / Liver Damage / Pregnancy Alcohol withdrawal excitation can exacerbate Epilepsy

GABA Drinks - Alcohol-Free drink with ‘plant-based’ active ingredients targeting GABA neurotransmission

Psychedelic Water

(Kava + Velvet Bean + Green Tea)

Kin Euphorics

(GABA + 5-HTTP + Rosea Root Extract + )

main psychoactive component of tobacco

nicotinic Ach receptor (agonist)

behavioural effects -> not understood

rewarding/addictive qualities -> increased DA release

enhanced cognition + attention -> increased Ach release

simulation + arousal -> increased NE release

acts on Ach in PNS

leads to increased SNS activity (increased HR + BP)

causes secretion of catecholamines like Epi from adrenal glands

nAch receptors become desensitized (increased tolerance) -> receptor levels increased -> may contribute to withdrawal Sx

1000+ Harmful ingredientsNicotine = Greatest concerns

Carbon Monoxide / Hydrogen Cyanide / Ammonia / Nitrosamines Tar → Polycyclic Hydrocarbons → Proven Carcinogens

Absorption: Depends on route of administration & pH -> look at graph

Distribution: Easily cross membranes (BBB, Placenta)

Cigarettes: reaches brain in 7-10 s

Elimination: CYP2A6 metabolism + Kidney Excretion Half-Life ≈ 1-2 hours -> 4 ½ rule: 4x2 = 8 hours to excrete all of it

nicotine is weak base

alkalinity increases absorption (why cigarettes have ammonia in them)

• Mimics Acetylcholine (Ach) on Nicotinic Receptors Only

• Low Dose Nicotine (N2 receptors in PNS/CNS) = Agonist

High Dose (can go to N1, but this is HUGE dose) = Antagonist

homomeric = low affinity for nicotine

heteromeric = high affinity for nicotine

Activation of nAchRs at Sympathetic Ganglia + Adrenal Medulla -> ↑ Epi & NE release -> ↑ BP + HR + Contractility -> Cardiovascular Diseases

look at graph

Destruction of cilliated columnar epithelium -> Replaced by squamous stratified (metaplasia!!) -> ↑ risk of infections & entry of toxic molecules

Carbon monoxyde toxicity

Pulmonary circulation impairments

Alveoli destructionLung Cancer

GI Effects

Parasympathetic Ganglia Activation -> increased GI secretions + motility

Gums & Teeth

Smoker’s Melanosis -> Teeth discoloration and falling

CNS/PNS Stimulant↑ Respiration & Sympathetic Arousal High doses → Convulsions Strong ↑ DA reward pathway

1 - Try Psychosocial Intervention alone

2 - Introduce NRT only if mother smokes 5+

cigarettes/day & #1 failed

3 - Limited safety data on Buproprion & Varenicline

Nicotine Replacement Therapy (NRT) > Smoking

NRT = Only Nictoine vs. Smoking = Lots of bad stuff Modest efficacy for smoking cessationClear benefit: ↑ Birth weight

Ectopic Pregnancies

Preterm or StillbirthLow birth Weight

Cognitive decline

Sudden Infant Death Syndrome

Tolerance to nausea & dizziness/ No Tolerance to cardiovascular effects

Common Abstinence Symptoms

Begin within 24h of cessation

May last for weeks to months

Abrupt cessation > Gradual tapering

Sx include: restless, eating more, anxiety, impatient, dizzy, remorse, insomnia....

Nicotine is very toxic / Less than 40mg can kill -> leads to paralysis because it depletes muscles from E needed cuz increased stimulation at neuromuscular junction

Nicotine & derivatives found in many insecticides

Major Causes:

Tobacco ingestion or Insecticides exposure

Symptoms:

Intense Cardiovascular + GI + CNS effects

Ex.: Vomiting / disturbed vision/ Irregular pulse Death by respiratory paralysis

Treatment:

No specific antidoteVentilatory support + Activated charcoal = Usual

Smoking damages almost every organ

Multiple Cancers (Lung, Oropharyngeal, Leukemia) Heart & Lung Diseases (COPD, Atherosclerosis)

T2DM / Cataracts / Pneumonias

• Tolerance to nausea & dizziness

• Not to cardiovascular effects

• Associated with withdrawal symptoms

• Symptoms greater if abrupt cessation

• Symptoms begin within 24h of stopping and may last for weeks to months

68% of adult smokers want to quit

55% of adult smokers have tried to stop

Success rate = 7.5%

Most try 5-7 times before succeeding

Counseling + Medication success ≈ 25%

20 mins: BP drops to level similar to before last cig

1 year: added risk of coronary heart disease is half that of a person who smokes

15 years: risk of coronary heart disease similar to someone who has never smoked

never too late to quit!

Most effective (always with psychological support) : Varenicline or Patch + Spray or Gum

side effects: itching, burning, redness, insomnia

advantages: nonprescription, steady level of nicotine, easy to use

disadvantages: cannot adjust dose if craving occurs, nicotine released more slowly

side effects: mouth + throat irritation, aching jaw, dyspepsia

advantages: nonprescription, user controls dose

disadvantages: unpleasant taste, requires proper chewing, can ruin dental work

side effects: mouth + throat irritation, rhinitis, sneezing, coughing, teary eyes

advantages: user controls dose, fastest nicotine delivery, highest levels

disadvantages: prescription, most irritating

Most effective smoking cessation aid available

Partial agonist to nicotinic receptors + Moderate DA release

Adverse Effects:

Common: Nausea & Insomnia Severe: Neuropsychiatric Effects (Ex.: Mood changes / Suicidality)

advantages: easy to use, no nicotine, most effective

disadvantages: prescription, neuropsychiatric disturbances

• Atypical Antidepressant

• CNS stimulant + ↓ Appetite

• ↓ Cravings & Nicotine withdrawal Sx

Hypothesised beneficial mechanism:

• NE & DA uptake inhibition

Adverse effects:

• Dry mouth & Insomnia

• Risk of seizures with high doses

Efficient alone, but most effective when combined with NRT Patch & Support

• Vaping is less harmful than cigarette smoking

• Vaping is still bad for your health

• The subjectively less toxic feel & range of flavors makes vaping very enticing for kids/teenagers

• Should be marketed as a smoking cessation method rather than simply another cigarette

• Majority of OUD startd with illicit usage

• Small minority from hospital exposure

• High rate of OUD among HCPs

• Primary cause: Easy drug access

IV Synthetic Opioids

- Formerly Heroin- Now stronger synthetic opioids (Ex.: Fentanyl, Carfentanyl)

Oxycodone

- Common starting point- Pills crushed, then snorted/ injected New formulations prevent dissolution

Meperidine

- Favored for abuse among HCP- Works best PO → No injection telltale signs

seconds -> initial rush: warmth, pleasure + relaxation

mins-hours -> prolonged sense of euphoria/well-being

initial first few doses -> prominent nausea + vomiting + dysphoria

Tolerance• Tolerance to: Euphoria / Respiratory Depression / Nausea

• No Tolerance to: Constipation / Miosis

• Cross-Tolerance among opioids but not with CNS depressants

Physical Dependence• Acute withdrawal: Intense & unpleasant but not life-threatening

• Long 2nd phase of withdrawal: Insomnia + Irritability + Fatigue

Opioid Overdose Triad

- Coma → Profound/No

arousal

- Pinpoint Pupils → May dilate later with hypoxia

- Respiratory Depression → ≈ 2-4breaths/min

Ventilatory Support + Naloxone

opioid antagonist

Reverses most effects of opioid agonists

Short Half-Life → Repeat doses until safe

Other Therapeutic uses: Neonatal & Postoperative Respiratory Depression

Methadone

Long-Acting Agonist → Safer + Milder withdrawal

Maintenance Tx: Subsitution without the tapering off

Suppressive Tx: ↑ Methadone dose until high tolerance

↓ Desirable effects (euphoria) & opioid cravings

Buprenorphine

Agonist-Antagonist

Maintenance Tx only

Smaller abuse potential: Available in general clinics

Safer than Methadone (Respiratory depression ceiling)

Naltrexone

Pure opioid Antagonist → Relapse prevention

Blocks all potential benefits → No incentives to abuse

No special training or certification required

Lasts ≈ 10-14 days:Step 1: Switch opioid of abuse to methadoneStep 2: Once stable, gradually taper off methadone

• Abstinence syndrome is milder (≈ moderate flu)

• Observe withdrawal symptoms to adjust methadone dosage

Direct Health Impacts

• Few direct health impacts

• Methadone maintenance therapy has been used for decades & allows individuals to lead successful social & professional lives

Indirect Health Impacts

• Lifestyle associated with opioid use

• Infections from impurities of street drugs + needle-sharing

• Accidental overdose• Injury due to violence

endocannabinoid system -> mood, appetite, memory, pain

THC binds to CB1 receptors -> gives stoned/high feelings

CBD does not bind to CB1 receptors, but can do allosteric inhibition (turn off CB1 for THC)

u can get different concentrations based on effects you want

sativa: supposedly more energizing (more THC?)

indica: supposedly more relaxing (more CBD?)

CBD: non-psychoactive, euro-protective, anti-convulsant, antioxidant, anti-psychotic, anti-inflammatory, anti-tumoral, minimal side effects

THC: psycho-active, relaxant, appetite stimulant, drowsiness, analgesic, euphoria, paranoia, anxiety

endocannabinoid system

System involved in:

• Inflammation & Pain Perception• Appetite Regulation• Memory / Thinking / Concentration • Movement & Motor coordination

CBD: allosteric inhibition @ CB1 (Expressed in CNS Psychoactive effects)

THC: strong agonist @ CB1

weak agonist @ CB2 (Expressed in immune system & hematopoietic cells)

bioavailability: 60% vs 6-20%

onset: 20-30mins vs 50 mins

duration: 3h vs 12h

cardio system:

- dose related tachycardia

- vasodilation/orthostatic hypotension

- red eyes

CNS

- decreased hippocampus + amygdala

lungs:

- acute: bronchodilation

- chronic: constriction

- marijuana smoke more carcinogenic than cigarette

reproductive system

- males: decreased spermatogenesis + testosterone

- females: decreased FSH, LH + Prolactin

- teratogen: impaired cognitive functions

Euphoria

Sedation

Hallucination (Only psychoactive Rx to produce all 3)

high dose

Hallucinations / Delusions / Paranoia / Intense Anxiety

Dissociative experience can trigger Psychosis-like state

low/moderate dose

Very Contextual: Previous experience / Route of Admin / Etc.

Innocuous: Relaxation / ↑ Humour & Appetite / Time seems to go faster

Dangerous: Impaired memory & motor coordination / Altered judgement

Chronic Use:

• Amotivational Syndrome

• Apathy / No interest in achievement & personal goals / Poor grooming

• Unknown cause: Not related to structural brain changes

Tolerance: Little to none

Dependence: Only in very high dosage

Alcohol -> one of most toxic out there

• 100,000+ overdose deaths/year

• ↑ Hostility & Aggression• Nutritional Deficiencies

Cannabis -> toxic but not as much as alcohol

• Practically no overdose death (ever)

• ↑ Appetite & Weight• Toxic psychosis• Dissociative phenomenas

Both

Impaired judgement & motor coordination

Cannabis use associated with:

• ↑ risk of symptoms for young individuals without any prior history of schizophrenia

• ↑ symptom duration for individuals diagnosed with schizophrenia

• ↑ risk of psychosis for individuals with stabilized schizophrenia

• Psychosis risk seems to depend on genetics

• May explain individual differences in subjective experience

-> interaction between genes + weed

Approved usage not for cannabis itself but for purified THC & some THC-analogs

Approved usage• Suppression of Chemotherapy-induced nausea & vomiting• Appetite Stimulation in AIDS patients• Multiple Sclerosis: Neuropathic pain relief + ↓ muscle tremors & spasticity

Unapproved usage• Glaucoma: May ↓ intraoccular pressure• But may also ↓ blood supply to optic nerve

NMDA glutamate receptor inhibition

Has weak effect on opiate receptors in dopamine system (like cocaine and heroin target)Also acts on neurotransmitter glutamate (brain uses this to communicate with each other, without it your brain would shut down)

At high doses: blocks glutamate -> effective sedative

Low doses: ramps up glutamate production -> hallucinate, losing touch with reality, help build new synapses between neurons

Could be 1 of best antidepressants ever

There is still a lot they don’t know -> because ketamine targets dozens of systems, it might be unclear sr what other effects are

Challenge is how to maintain they new connections formed everyday? Do they need to give ketamine repeatedly -> cannot give ketamine everyday, that’s substance of abuse cuz it would harm the brain

Amnesia + Immobility

Odorless + Tasteless + Colorless

In high doses:

Analgesia / Sedation Amnesia / Immobility

In recreational doses:

Visual & Hearing distortions

Feeling of body detachment

Dissociation of self & environment

Injectable anesthetics used for humans & animals **Only anaesthetic that ↑ CO**Snorted for recreational purposes

Fast & Short action: Peak: few minutes / Duration: 1h

Moderate Dosage: K-hole experience

Produce dream-like state or Near-death experience of floating away from body Either described as enlightening or terrifying

High Dosage:

Hallucinations & DeliriumPotential respiratory arrest or cardiovascular collapse

Mechanism of Action = KetamineBlock NMDA receptors in cerebral cortex + limbic systemKinetics: Very lipid-sobluble, Longer T1/2 than Ketamine

Low to Moderate Doses: Alcohol-like effects: ↓ inhibition / euphoria Disorganised thoughts & altered perception

High-Dose: Severe hallucinations & SCZ-like psychosis Coma / Seizures / Rhabdomyolysis

Toxicity Management: Best = Isolation from external stimuli Ventilation support & IV Diazepam for seizures ‘Talking down’ or antipsychotics are ineffective

magic mushrooms -> psilocybin

acid -> LSD

ayahuasca -> DMT

produce dreamlike states without loss of consciousness

• Boundaries between ‘self’ & ‘non-self’ fade• Perception of unity & harmony with the world/cosmos • Popular in the world of meditation/mindfulness

• 5-HT2 agonist / PO Admin• Onset: 1-2h / Duration: Few hours

• Neuromuscular: Tremor / ↓ coordination

• Sympathetic activation: ↑ HR & BP

effects are more subjective/behavioural

• Alterations in thinking , feelings & perceptions

• Can be terrible or sublime• No way to guess – ‘It’s a trip!’

Common:• Synesthesia & Kaleidoscopic images• Overwhelming intensity of emotions• Transient sense of insight & attitude changes

• Rapid tolerance to subjective & behavioral effects • Cross-tolerance between Psylocibin & LSD• No X-tolerance with DMT (ayahuasca), THC or

• No Abstinence Syndrome

• No risk of addiction

• No direct death from overdose• Acute panics (‘bad trips’) common• In a small % recurrent episodic visual disturbances

• Others: Prolonged SCZ-like psychotic reactions /

Depression Dissociative experiences / Persistent fear

Party drug also known as ‘Molly’

• Low-dose: LSD-like psychedelic effects

• Higher-dose: Amphetamine-like stimulant effects

Main Recreational Usage: Good sensations

• Feelings of elevated mood & sensory perception

• Heightened sensitivity to music

• ↓ Anxiety & ↑ Interpersonal comfort/closeness

• Increases release of 5-HT and DA

• Blocks reuptake of 5-HT and DA

low dose affects more 5HT

high dose affects more DA

• Promising results for Tx of PTSD & Severe anxiety in cancer patients

• Benefits from ↓ fear of death & anxiety of the unknown

1)5-HT Neurotoxicity

2)Dehydration-associated hyperthermia

• Leads to hyponatremia & rhabdomyolysis

• Management: Rapid cooling + Rehydration + Dantrolene

• Prevention: Drink high amounts of fluids

Warning: MDMA also promoteswater-retention!

3) Amphetamine-like toxicity

↑ HR & BP → Risk of heart attacks

4) others

seizures/panic attacks/hallucinations