what are different ways substance use is a burden to Canada?
it affects:
healthcare costs
lost productivity costs
criminal justice costs
other direct costs
what is happening to the trend of substance abuse?
trend is on the rise
what are the 3 worst drugs of abuse in terms of harms caused by drugs?
alcohol
heroin
crack cocaine
what are the 3 least worst drugs of abuse in terms of harms caused by drugs?
mushrooms
buprenorphine
LSD
what is the textbook definition of substance abuse?
using a drug in a fashion inconsistent w/medical or social norms
what is the APA definition of substance abuse?
cluster of cognitive, behavioural, physiological Sx indicating that the person continues using the substance despite significant substance-related problems
why is the definition of substance abuse a difficult concept?
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
what is tolerance?
given dose produces smaller response then when initially taken -> develops over regular/chronic use of drug
decreased drug response from repeated doses
what is cross-tolerance?
tolerance to one drug produces tolerance to other similar drug -> tolerance to 1 opioid = all opioids
what is physical dependence?
abstinence/withdrawal Sx if drug is discontinued -> body adaptation to long term physiological drug effects
what is psychological dependence?
intense motivational cravings to consume drug
what is cross-dependence?
ability of a drug to support dependence to another drug -> methadone alleviates Sx of fentanyl withdrawal
what are withdrawal Sx?
Sx associated w/drug discontinuation when dependent -> usually opposite of the drug effects
what is pharmacodynamic tolerance?
long term receptor regulation (body is less sensitive)
an increase in minimum effective concentration
rightward shift of dose-response curve
may decrease max efficacy
what is hysteresis?
special short term dynamic tolerance
basically a "lag phase"
what is metabolic tolerance?
altered (increase or decrease) drug metabolism (increased clearance of drug or reduced uptake)
usually decrease duration of response
what is tachyphylaxis?
special short term kinetic tolerance
what are withdrawal/rebound effects?
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
how is substance use disorder diagnosed?
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
what is the reward pathway (DA pathway) in the brain?
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
how is the reward pathway regulated?
VTA is the driver -> promotes behaviour
pre frontal cortex -> inhibitor, controls impulsion
what happens to the regulation of reward pathway in SUD?
dysregulation
repeated substance use -> neurobiological changes (I.e. DA release) -> behaviour is reinforced
the VTA has more control and prefrontal cortex has less control
what is the cycle of addiction?
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
what is the pure choice design for the SUD studies?
food or drug always available -> direct comparison
what is the working cost design for the SUD studies?
increasing workload to get dose -> measures addictive power
what did the rat park experiment show?
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
what is the development of SUD?
usually gradual addiction
curiosity exposure -> occasional usage -> compulsive usage
what are 6 contributing factors to SUD development?
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
what are the goals of SUD treatment?
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
what are the 4 approaches to Tx for SUD?
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
explain alcohol absorption.
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
explain alcohol distribution.
non polar -> easily crosses BBB
water soluble -> higher effects on females (higher percent of body fat + lower body weight
how is alcohol metabolized?
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
why do patients of asian descent have a flushed face when drinking alcohol?
hypoactive ALDH -> buildup
how is alcohol excretion?
zero order kinetics:
average elimination rate = 1 drink/hour
easy to drink faster than its elimination
therapeutic index = 4 (very very low)
what are the alcohol dynamics?
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
what are alcohol acute effects?
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
what happens with alcohol poisoning ?
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
what happens with alcohol tolerance?
Tolerance develops to all effects EXCEPT Respiratory Depression
• Cross-Tolerance with Barbiturates & Benzos (also acts on GABA) / NOT Opioids (does not act on GABA)
what happens with alcohol dependence?
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
how is AUD defined in terms of weekly?
14+ drinks for males
7+ drinks for females
also look at DSM-5 criteria
what is alcohol withdrawal syndrome?
risk of AUD
• Potentially fatal due to cardiovascular collapse• Lasts ≈ 5-7 days (increasing severity)• Symptoms: Vomiting / Hallucinations / Intense Tremors / Seizures
what are some AUD common consequences?
• Major cause of car crash & industrial accidents • Psychological dysfunctions / Malnutrition / Other harmful effects discussed earlier
what is management of AUD?
Benzodiazepine = Best option
Very safeStabilizes vital signs ↓ Sx intensity↓ risk of seizures &
hallucinations
can also use beta blockers, alpha agonists, anti epileptic
what is AUD relapse prevention?
Naltrexone (opioid antagonist)
• Most effective• ↓ Reward effect & cravings
Disulfiram -> inhibits ALDH -> increases acetaldehyde -> increases negative effects
• Moderate efficacy
• Avoid any alcohol (sauces, lotions, etc.)
what are standard drink references?
12 oz beer
12 oz cooler
5oz wine
1.5oz spirits
what is alcohol risk continuum?
0 drinks = no risk
1-2 = low risk
3-6 = moderate risk, cancer risk increase
>7 = high risk
what are pregnancy + breastfeeding considerations for alcohol?
• Pregnancy: No known safe amount of alcohol use
• Breastfeeding: Not drinking alcohol is safest
what are some gender facts on alcohol?
Males: Far more injuries, violence and deaths
Females: Above the moderate risk zone, health risks increase more steeply
what did the study on the impact on lifespan of alcohol show?
• Moderate drinkers have ↑ lifespan• Correlation ≠ Causation
• Conclusion: Few drinks now and then can be ok but don’t start just for that!
what did the cardiovascular studies show?
studies have consistently proposed cardiovascular benefits associated with light alcohol consumption.
what is alcoholic liver disease?
hepatotoxicity
major cause of fatal cirrhosis (permanent damage)
look at drawing in slide of MoA
what is link between alcohol + cancer?
alcohol is carcinogen that can cause at least 7 types of cancer
what can happen if you drink alcohol while pregnant?
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!!
what is link between alcohol + breastfeeding?
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.
what is link between alcohol + cardiovascular?
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)
what are other physiological effects of alcohol?
Gastritis & Pancreatitis
Hypoglycemic Effect
↓ Gluconeogenesis + Impaired Glycemia Feedback
Pro-Osteoporosis Effect
↓ Growth Hormone↓ Bone Deposition & ↑ Resorption
↑ Snoring & Sleep Apnea
what are interactions of alcohol?
CNS Depressants: Additive Effects
Ex.: Benzodiazepines / Opioids ↑ Respiratory depression
Antihypertensive Rx
Low alcohol ↓ BP vs. High alcohol ↑↑ BP
NSAIDs: ↑ Gastric Bleeding
what are contraindications of alcohol?
Peptic Ulcers / Liver Damage / Pregnancy Alcohol withdrawal excitation can exacerbate Epilepsy
what are psychoactive alcohol free drinks?
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 + )
what is nicotine? where does it act?
main psychoactive component of tobacco
nicotinic Ach receptor (agonist)
what are effects of nicotine on brain?
behavioural effects -> not understood
rewarding/addictive qualities -> increased DA release
enhanced cognition + attention -> increased Ach release
simulation + arousal -> increased NE release
what are effects of nicotine on PNS?
acts on Ach in PNS
leads to increased SNS activity (increased HR + BP)
causes secretion of catecholamines like Epi from adrenal glands
what happens with prolonged nicotine intake?
nAch receptors become desensitized (increased tolerance) -> receptor levels increased -> may contribute to withdrawal Sx
what ingredients are in tobacco?
1000+ Harmful ingredientsNicotine = Greatest concerns
Carbon Monoxide / Hydrogen Cyanide / Ammonia / Nitrosamines Tar → Polycyclic Hydrocarbons → Proven Carcinogens
what are the kinetics of nicotine?
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
what is link between nicotine and alkalinity?
nicotine is weak base
alkalinity increases absorption (why cigarettes have ammonia in them)
what are the dynamics of nicotine?
• 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
what are particularities of nicotinic receptors?
homomeric = low affinity for nicotine
heteromeric = high affinity for nicotine
what are cardio effects of nicotine?
Activation of nAchRs at Sympathetic Ganglia + Adrenal Medulla -> ↑ Epi & NE release -> ↑ BP + HR + Contractility -> Cardiovascular Diseases
look at graph
what are resp effects of nicotine?
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
what other resp effects of nicotine?
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
what are the guidelines for smoking + pregnancy?
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
what are risks of smoking + pregnancy?
Ectopic Pregnancies
Preterm or StillbirthLow birth Weight
Cognitive decline
Sudden Infant Death Syndrome
what happens with nicotine tolerance?
Tolerance to nausea & dizziness/ No Tolerance to cardiovascular effects
what happens with nicotine dependence?
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....
what is acute nicotine poisoning?
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
what is chronic smoking toxicity?
Smoking damages almost every organ
Multiple Cancers (Lung, Oropharyngeal, Leukemia) Heart & Lung Diseases (COPD, Atherosclerosis)
T2DM / Cataracts / Pneumonias
what is nicotine tolerance?
• Tolerance to nausea & dizziness
• Not to cardiovascular effects
what is nicotine dependence?
• Associated with withdrawal symptoms
• Symptoms greater if abrupt cessation
• Symptoms begin within 24h of stopping and may last for weeks to months
what are some facts about smoking cessation?
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%
what are some benefits of quitting?
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!
what are some smoking cessation aids?
Most effective (always with psychological support) : Varenicline or Patch + Spray or Gum
what are facts about nicotine patch?
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
what are facts about nicotine gum?
side effects: mouth + throat irritation, aching jaw, dyspepsia
advantages: nonprescription, user controls dose
disadvantages: unpleasant taste, requires proper chewing, can ruin dental work
what are facts about nicotine nasal spray?
side effects: mouth + throat irritation, rhinitis, sneezing, coughing, teary eyes
advantages: user controls dose, fastest nicotine delivery, highest levels
disadvantages: prescription, most irritating
what is varenicline?
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
what is bupropion?
• 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
what are some facts about e-cigs and vaping?
• 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
how does opioid use disorder (OUD) start? with who?
• Majority of OUD startd with illicit usage
• Small minority from hospital exposure
• High rate of OUD among HCPs
• Primary cause: Easy drug access
what are the preferred drugs for OUD?
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
what are the acute effects of OUD?
seconds -> initial rush: warmth, pleasure + relaxation
mins-hours -> prolonged sense of euphoria/well-being
initial first few doses -> prominent nausea + vomiting + dysphoria
what are the long term effects of OUD?
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
what happens during an opioid overdose? what is the treatment?
Opioid Overdose Triad
- Coma → Profound/No
arousal
- Pinpoint Pupils → May dilate later with hypoxia
- Respiratory Depression → ≈ 2-4breaths/min
Ventilatory Support + Naloxone
what is naloxone?
opioid antagonist
Reverses most effects of opioid agonists
Short Half-Life → Repeat doses until safe
Other Therapeutic uses: Neonatal & Postoperative Respiratory Depression
what is the long term management of OUD?
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
what is the OUD detox method using methadone?
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
what are the direct + indirect health impacts of OUD?
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
what system does cannabis act on?
endocannabinoid system -> mood, appetite, memory, pain
what is difference between THC and CBD?
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