PSYO 335 Drugs and Behaviour PDF

PSYO 335: Drugs and Behaviour Sept 3 2024 Week 1.1: What is a drug? -​ Define: a substance that alters the physiology of the body but is not a food or a nutrient -​ Psychoactive drugs:...

PSYO 335: Drugs and Behaviour Sept 3 2024 Week 1.1: What is a drug? -​ Define: a substance that alters the physiology of the body but is not a food or a nutrient -​ Psychoactive drugs: -​ Cross the blood-brain barrier -​ Act upon the central nervous system -​ Affect brain function -​ Change perception, mood consciousness, cognition, behaviour -​ Used recreationally entheogenically and medically -​ Basic Pharmacology: -​ Names of drugs: chemical, generic, trade, and street name -​ Drug Names: -​ A drug’s chemical name reveals its chemical composition and molecular structure -​ Pharmaceutical companies also may be patent brand names, or trade names, for their product -​ Generic drugs: -​ Contain same active ingredients as the original brand name drug -​ Must be pharmacologically equivalent -​ Naming convention -​ During development and marketing, pharma companies can patent a drug for a certain time so that no other company can sell it (~20-year period) -​ Pharma company sells drug under the trade name, proprietary name, or brand name -​ No other company can use that name -​ The trade name for diazepam is Valium -​ Excipients: coatings, colouring -​ Carrier medium: -​ USA – selling 100 doses of pure LSD = minimum sentence 15 years Sept 5 2024 Week 1.2: Pharmacodynamics -​ Define: The study of what a drug does to the body:  -​ Describing doses: -​ Milligrams : 1/1000 of a gram -​ Doses given in accordance to body weight -​ Dose Response Relationships: -​ To determine the effect of a drug, we have to study several doses and measure the change in some response -​ Relationship between dose and response is called the dose-response curve (DRC) -​ Important characteristic of DRC is slope -​ Refers to the most linear central part of the curve; how sharply the effect changes with each change in does -​ If a small change in dose produces a large change in effect the slope is steep -​ If large changes in dose produces small changes in effect, the slope is shallow -​ Describing Doses: -​ ED50: The median effective dose -​ The dose that is effective in 50% of the subjects tested -​ LD50: The median lethal dose -​ The dose that was lethal in 50% of the subjects tested -​ -​ One curve shows the percentage of animals in each group that lost consciousness (ED); the other curve shows the percentage that died at each dose (LD) -​ Therapeutic index (TI): -​ TI = LD50/ED50 -​ The greater the TI the safer the drug; the difference between the desired effect and the undesired or lethal effect is larger -​ To be safer the TI can be calculated by using the LD1/ED99 -​ The Lower the TI the lower the safety: -​ THC → 1000, Morphine → 70, Cocaine → 15, Alcohol → 10, Heroin → 6 -​ Other factors to consider – ease and speed of consumption  -​ Therapeutic Window: -​ The therapeutic window is a range of blood concentration of a medicine above a level that is ineffective (therapeutic level) and a level that has a toxic side effects -​ Complicated by absorption/excretion curves -​ Potency and Effectiveness:​ -​ The extent of the drugs effect -​ Potency: differences in the ED50 -​ Effectiveness: differences in the maximum effect that drugs will produce at any dose -​ Effectiveness: -​ The maximum effect obtainable with additional doses producing no effect -​ Some drugs may be potent but they might never be able to produce a peak response no matter how much is given -​ Aspirin vs morphine -​ A drug that is more effective can produce a greater peak or maximum, effect than a drug that is less effective -​ Primary and Side Effects: -​ primary/main effect: intended result in treatment -​ Side effect: unintended; may be wanted or may be harmful -​ Addiction -​ Drug Interactions: -​ Drug antagonism: one drug diminishes the effect of the other -​ Additive effect: shifts the DRC to the left -​ Superadditive effect/potentiation/agonism: combining drugs increases the effect -​ Physiological -​ Alcohol and sedatives -​ Behavioural -​ Alcohol and stimulants Sept 10 2024 Week 2.1: Pharmacokinetics -​ “What the body does to a drug”: -​ Administration: how a drug gets into the body -​ Absorption: how a drug gets into the blood -​ Distribution: how it travels -​ Binding at sites of action: where the drug needs to go -​ Elimination: how the drug leaves -​ Administration: -​ Parenteral – under the skin -​ The vehicle is needed, liquid -​ Subcutaneous – injected to form a bolus just under the skin -​ Skin popping -​ Intramuscular (IM) – needle inserted into the muscle -​ Intravenous (IV) – injected into the vein -​ Mainlining -​ Other parenteral routes: -​ Intraperitoneal (gut), intraventricular (brain) -​ Absorption from parenteral sites: -​ Reliant on blood flow -​ IV is direct enters blood stream via capillaries -​ # of capillaries in an area influences speed of absorption -​ Diffusion: -​ Substances moves from are of high to low concentration -​ Depot injections -​ Slowly dissolves into the body over a long period of time -​ Inhalation of Gases: -​ The lungs -​ Efficient gas exchange system -​ Oxygen -​ Carbon dioxide -​ Artery from gear to brain without the liver -​ Inhalation of Smoke and Solids:​ -​ Burning of dried plant material -​ Tobacco -​ Vapour and tiny particles of ash -​ Not exhaled like gases -​ Popular among humans but under-studied -​ Difficult with other animals -​ According to Dr. Ryan McLaughlin: -​ High does admin of synthetic cannabinoids is not a model for the effect of cannabis -​ Route of admin is important variable in preclinical cannabis research -​ Injection approaches produce dramatic elevation in bioavailability that is unlike inhaled cannabis -​ If studying acute effects inhalation are best model to use -​ Sniffing of drugs: intranasal admin – cocaine -​ Oral administration – peroral, buccal membranes, chewing tobacco -​ Suppository – unconscious, vomiting -​ The Digestive System:  -​ Drugs absorbed in intestines -​ Faster on empty stomach -​ To reach capillaries must pass intestinal membranes -​ Made of lipid bilayer -​ Lipid solubility: -​ Olive oil partition coefficient -​ How much drug is in water versus oil -​ Ions are not lipid soluble -​ Level of ionisation determines degree of absorption -​ Can take place in the gut via metabolism – onset of effects -​ Transdermal Administration:​ -​ Absorbed through the skin -​ Epidermis, keratin -​ Lipid soluble → but waterproof! -​ Nicotine patch -​ Excretion:​ -​ Excretion and Metabolism:​ -​ The Liver: Enzymes -​ Catalysts – change molecular structure -​ Alcohol dehydrogenase -​ Restructuring molecules aka Metabolism -​ Metabolites: -​ >useful/ionised = easily excreted -​ Detoxification: -​ The metabolic process -​ First Pass Metabolism: -​ Any drug absorbed from the digestive system will pass through the liver before going anywhere else in the body -​ Subjected to liver enzymes -​ Rate of excretion -​ Excretion most efficient at higher blood levels -​ Half-life -​ First Pass Metabolism – Rate of Excretion (half life) -​ The top panel shows a typical excretion curve for a drudge like nicotine which has a half life of about 30 minutes -​ The bottom panel shows the excretion function for alcohol which is excreted at a constant rate (abt 15 mg/100 ml of blood per hour)  -​ Because the excretion function for alcohol is a straight line, the concept of half life does not apply -​ The Kidneys:​ -​ Filter everything from blood and reabsorb what is needed -​ Lipid soluble passed back to blood -​ Unless actively transported out -​ Ionised non-lipid-soluble substances passed to bladder -​ Unless actively reabsorbed -​ Ph influences – blood basic/urine acid = bases excreted -​ Factors that alter drug metabolism: -​ Important determinant of individual differences in effects -​ Stimulation of Enzyme Systems -​ Enzyme induction -​ Responsible for development of metabolic tolerance -​ Depression of enzyme systems -​ Metabolism of alcohol -​ Disulfiram (antabuse) → makes you throw up -​ Used to prevent drinking -​ Age: -​ Young not able to metabolise the dose of an adult -​ Incomplete enzyme development -​ Infant with drugs in system at birth -​ Elderly – less efficient liver and kidneys -​ Species: -​ Alcohol dehydrogenase -​ Rats – 60% versus guinea pig – 160% vs. humans -​ Pharmacodynamics: -​ Therapeutic window: a range of blood concentrations of a medicine above a level that is ineffective (therapeutic level) and a level that has toxic side effects (toxic level) -​ Complicated by absorption/excretion curves  Sept 12 2024 Week 2.2: Research Design -​ Level of Arousal: -​ One of the earliest ways of classifying drugs by whether they increase or decrease arousal -​ Stimulants or “uppers” versus depressants or “downers” -​ True Experiment: -​ IV: manipulated event → drug -​ DV: observed event → behaviour -​ Experimental Research Design: -​ Within-subjects: stable baseline -​ Same person every time so -​ Between-subjects: equivalent groups -​ Research Design: -​ Placebo Effect → The Importance: -​ Measuring behaviour in nonhumans -​ Spontaneous Motor Activity (SMA) -​ Inclined plane test -​ Muscle tone -​ Elevated plus maze -​ Anxiety -​ Paw lick latency test -​ Analgesia -​ Reinforcing properties of drugs -​ Progressive ratio: -​ Breaking point -​ Organism will stop responding -​ Choice: two levers; one has consequence -​ Conditioned place preference: animal will spend time in area of reinforcement -​ Schedules of Reinforcement: -​ Pattern that determines when reinforcements are to be given -​ Avoidance-escape task -​ Antipsychotic drugs reduce avoidance not escape -​ Punishment -​ BZ increase behaviour repressed by punishment -​ Problems with rate of responding -​ Effect interfere Sept 17 2024 Week 3.1: History -​ History of Drug Laws: -​ Proponents of drug regulation typically refer to the protection of the vulnerable and the maintenance of cultural values -​ Critics of drug policy cite institutionalised racism and indirect pursuit of socio political interests -​ Efforts to regulate the use and distribution of psychoactive substances can be traced back to antiquity -​ No single attribution captures the confluences of social, political and individual forces that influence policy -​ Plato:Prohibiting alcohol use for men younger than 18 and regulating use for men younger than 30 -​ Christianisation of the Roman Empire and Eruope a variety of nonalcoholic psychoactive substances fell into disfavour and were associated with Pagan religious traditions -​ The Inquisition outlawed cannabis use in the 12th and 13th centuries -​ Prohibited indigenous people from the ceremonial use of psychoactive drugs and drug users continued to endure persecution as witches until the late 17th century -​ Coffee of africa introduced to the Middle East in the 15th century -​ Considered to be an intoxicant and was therefore prohibited -​ Soon accepted in Middle Eastern Culture and even found sacred use -​ 16th century church banned coffee cited as a beverage of “infidels” -​ 1600 the Vatican declared coffee to be sacrosanct and coffee drinking was established throughout Europe by the 17th century -​ In the 17th century many european states prohibited tobacco (New World) use of several papal edicts were issued against tobacco -​ Russia germany turkey and china all executed tobacco users -​ 18th Centurt “Age of Reason” relatively liberal -​ China bans opium -​ Opium wars with Britain -​ Early example of international intervention -​ 1868 British Pharmacy Act -​ Opium sold only by pharmacists -​ 1875 — Smoking opium outlawed in US (CHinese) -​ Early 20th century -​ US most substances were readily available -​ 1914 Harrison Narcotic Act: -​ Tax on opium and cocaine (African Americans) -​ By 1920s mass incarceration -​ Attempted tobacco prohibition -​ Alcohol prohibition (end 1933) -​ 1930:  -​ Great depression -​ Antimexican sentiment -​ 1937 Marihuana tax act -​ 1961: -​ UN Single Convention on Narcotic Drugs -​ 1970: -​ Comprehensive Drug Abuse Prevention and Control Act -​ Classified drugs into five schedules with escalating penalties based on potential for abuse -​ Nixon’s war on drugs -​ History of Drug Laws: -​ Harm reduction -​ Decrim personal use in Spain, Italy and Portugal -​ Heroin maintenance in Germany, Netherlands, Switzerland -​ Hard line remains in US, Russia, and Iran -​ Developments: -​ Heroin maintenance drug courts -​ “The violence in Mexico, the HIV associated with needle sharing in Russia and the acquisitive crime of addicts in Britain are all approximately the result not of drug consumption but of the conditions that have been created by prohibition -​ Vienna Declaration of 2010: -​ Implement and evaluate a science based public health approach to address the individual and community harms stemming from illicit drug use -​ Decriminalise drug users, scale up evidence based drug dependence treatment options and abolish ineffective compulsory drug treatment centres that violate the universal declaration of human rights -​ Basing drug policies on scientific evidence will not eliminate drug use or the problems stemming from drug injecting however reorienting drug policies towards evidence based approaches that respect, protect and fulfil human rights has the potential to reduce harms deriving from current policies and would allow for the redirection of the vast financial resources towards where they are needed the most: implementing and evaluating evidence based prevention, regulatory, treatment and harm reduction interventions -​ The Moral Model: ​ -​ Philosophical foundation of the “war on drugs” -​ Use of prohibited drugs is purposeful unethical and immoral conduct -​ Users are blameworthy and selfish hedonists -​ Justified targets of punishment -​ Deserving of health, employment and legal problems -​ Punishment is a viable deterrent -​ Pros: -​ Simple, absolute, reaction is straightforward, reinforcing for abstainers -​ Cons: -​ Inconsistent with evidence, expensive, pathogenic, cruel -​ Alternatives: -​ Medical model: -​ Addiction is like other diseases -​ Heritability -​ Course -​ Primary relative to other disorders -​ Reduces blame → increases treatment -​ Loss of control -​ Progressive -​ Psychodynamic model: -​ Developmental experiences lead to psychic conflict -​ Conflict is painful and this pain is numbed by drug use -​ Drug use is secondary – self medication -​ Family systems: -​ Addresses familial transmission of substance use -​ Parental addiction causes disequilibrium -​ Expressed by dysfunctional behaviour of oher family members -​ Adoption of unhealthy roles -​ The identified client is representative of dysfunctional family -​ Modelling of substance use -​ Learning: -​ Classical associative learning -​ ABCS -​ Drug use represents a system of positive and negative reinforcement -​ Social learning -​ Expectancies -​ Self efficacy in the face of anxieties and need  -​ Social pressure -​ Substance use outcomes -​ Failure to habituate to anxiety -​ Biopsychosocial: -​ Substance use is multi-determined -​ Diathesis stress -​ Bio​ -​ Heritable factors related to drug metabolism -​ Psycho -​ Personality traits -​ Psychopathology -​ Social -​ Peer groups -​ Community/family norms -​ Public health model and harm reduction -​ Use on a continuum from excess to abstinence -​ Harmful consequences also on a continuum -​ Safer route admin -​ Alternative, safer substances -​ Reduce frequency of drug use -​ Intensity of drug use -​ Reduce harmful consequences of drug use Sept 24 2024 Week 4.1: Tolerance -​ Tolerance: -​ The decreased effectiveness or potency that results from repeated administrations -​ The necessity of increasing the dose of a drug in order to maintain its effectiveness after repeated administrations -​ Effects vs drugs: -​ Multiple rates/mechanisms -​ Cross tolerance: -​ Common mechanisms? -​ Acute tolerance -​ Rise vs. fall – BAL curve -​ Single admin of a drug so to say -​ Mechanisms of Tolerance: -​ Metabolic/dispositional/Pharmacokinetic tolerance -​ Enzyme induction -​ General/nonspecific tolerance  -​ At site of action -​ Physiological tolerance (cellular): -​ Homeostasis -​ Compensatory – maintain set point -​ Neurotransmitters up/down regulation -​ Different rates/effects -​ Specific tolerance -​ Downstream -​ Functional Disturbances: -​ Evidence for homeostatic effects – feedback loop -​ Anorexic effects – stimulants -​ Hypothermic tolerance only develops in cold – alcohol -​ Withdrawal: -​ Withdrawal symptoms and physical dependence -​ Physiological changes that occur when the use of a drug is stopped or the dosage is decreased -​ Cross dependence -​ Dependence = physical dependence = psychological dependence = withdrawal -​ Psychological dependence = no withdrawal -​ Readjustment related to tolerance -​ A-B compensatory processes time lag -​ Hangover: -​ Aftermath of the acute effects of a drug -​ Associated effects -​ DEHYDRATION -​ Withdrawal – Opponent Process Theory:  -​ -​ Conditioning: Tolerance and conditioning -​ Drug response based on classical conditioning -​ Unconditioned stimulus (UCS): the drug -​ Unconditioned response (UCR): vomiting -​ Conditioned stimulus (CS): saline -​ Single trial learning – peppermint schnapps -​ Conditioned response (CR): vomiting -​ Conditioned drug tolerance: -​ Tolerance only in those areas associated with substance use -​ Heroin overdose: -​ 64% of rats in novel environment OD vs 32% in conditioned environment -​ Conditioned compensatory responses and withdrawal -​ Relapse triggers -​ Place that you've used before will trigger desire to use again -​ Tolerance based on operant conditioning -​ Alcohol and motor tasks -​ Feedback accelerates tolerance -​ Sensitization: -​ sensitisation/reverse tolerance: -​ An effect of a drug increases with repeated administrations -​ Much less common than tolerance -​ Long lasting -​ Cross sensitisation: -​ Stress can sensitise  -​ Mesolimbic dopamine system Sept 26 2024 Week 4.2: Guest – Neuro Lecture -​ The Neuron: -​ Nucleus -​ Membrane -​ Cell body -​ Dendrites → receive signals -​ Axon → send signals -​ Myelin sheath -​ -​ Resting potential: potential difference across the membrane -​ A relative value – difference between inside of cell and outside of cell -​ Outside neuron = 0 millivolts (mV) -​ Maintained by ion flow -​ Possess an electrical charge -​ RMP = -70 mV -​ More positive ions outside than inside neuron -​ Resting membrane potential: -​ Active transport mechanism: -​ Ion pump 3 Na+ out and 2 K+ in = overall negative charge -​ Ion channels -​ Places for passage across impermeable membrane -​ Different channels for different ions -​ Gated – depend on stimulus with secret passcode… a substance that binds to receptor like key and open sit up ** how a lot of drugs work -​ Non gated – slower than the pump -​ Resting potential and Action potential: -​ The All-or-None law: -​ Principle that action potential will always be the same -​ Stimulation of the Axon -​ Action potential: -​ The breakdown and restoration of the resting potential  -​ Threshold: -​ Voltage gated ion channels open – -​ Na+ rushes in until charge turns + -​ K+ leaves -​ Depolarisation: -​ Moves towards zero and positive numbers -​ Hyperpolarization: -​ Moves further away from zero – more negative -​ Getting the charge of the inside of the cell closer to the outside -​ -​ Synapse: -​ Information is transferred between neurons -​ Action at a synapse: -​ Neurotransmitter release -​ Bind at receptor sites -​ Lock and key -​ Presynaptic neuron receives, post synaptic neuron sends -​ -​ Excitation: -​ Excitatory postsynaptic potential (EPSP) -​ Depolarisation of the postsynaptic membrane -​ Inhibition: -​ Inhibitory postsynaptic potential (IPSP) -​ Harder for the cell to produce action potential -​ Summation of Excitation and Inhibition: -​ Spatial summation  -​ 2+ more neurons release transmitters onto the same target neuron -​ Temporal summation -​ A single presynaptic neuron sends multiple signals to the postsynaptic neuron over short time -​ Terminating synaptic action → reuptake -​ Resting potential and Action potential: -​ Second messengers: -​ Slower than receptor gated ion channels -​ Special molecule is released into the postsynaptic cell -​ -​ Synapse: -​ Presynaptic effects of neurotransmitters → autoreceptors -​ Neuromodulators → complex actions more subtle than neurotransmitters -​ Neurotransmitters: -​ Acetylcholine (ACh) -​ Memory and learning/reward -​ General activation -​ Destroyed by acetylcholinesterase -​ Cholinergic synapses/receptors -​ Nicotinic -​ Stimulated by nicotine -​ Blocked by curare, botox -​ Muscarinic: -​ Stimulated by muscarine – fly agaric/Amanita Muscaria -​ Blocked by atropine (belladonna, Mandrake) -​ Scopolamine (Jimson weed, Datura) -​ Monoamines:​ -​ Catecholamine -​ Tyrosine-precursor -​ L-Dopa → Dopamine → Norepinephrine → Epinephrine -​ Indolamine: -​ Tryptophan → serotonin  -​ Destroyed by -​ Monoamine Oxidase (MAO) -​ catechol-O-methyltransferase (COMT) -​ Reuptaken (unlike ACh) -​ Stimulants – accelerate release -​ Cocaine – blocks reuptake -​ Antidepressants = SSRIs, MAOIs -​ Receptor sites: -​ Each monoamine has several -​ Dopamine (6) -​ Serotonin (4 w/ subtypes) -​ Amino Acids: -​ Gamma-Aminobutyric Acid (GABA) -​ Inhibitory -​ Opens CI-channels -​ Reduces likelihood of action potential -​ Barbiturates and benzos -​ Different GABA receptors – different effects -​ Alcohol mimics -​ Glycine – also inhibitory, blocked by caffeine -​ Glutamate: -​ Excitatory -​ Blocked by Ketamine, Phencyclidine (PCP), Alcohol -​ Peptides: -​ Opioid-type peptides (Endorphins, Enkephalins) -​ Activate same receptors as morphine -​ Endocannabinoids -​ Nervous system: -​ Peripheral Nervous System (PNS) -​ Somatic Nervous System: -​ Conscious senses and voluntary muscles -​ Acetylcholine @ neuromuscular junction – control muscles -​ Autonomic Nervous System (ANS) -​ Automatic processes and unaware -​ Sympathetic Nervous System: -​ Fight or flight response -​ epinephrine/adrenaline -​ Stimulated by cocaine and amphetamine -​ Parasympathetic Nervous System -​ Central Nervous System: -​ Spinal cord → serves as a relay station -​ Brain → 100 billion neurons… 1000 synapses out/ 10000 in -​ The Brain: -​ Medulla: -​ Autonomic NS -​ Depressed by alcohol, opiates, barbiturates -​ Breathing – shut down by toxic dose -​ Vomiting centre -​ Reticular Activating System (RAS) -​ Spreading excitation to cortex + -​ Inhibited by GABA -​ Raphé system: -​ Sleep centre (active process) -​ Serotonin -​ Mood – action points for SSRIs -​ Locus Coeruleus: -​ Over half of norepinephrine neurons -​ Mood – anxiety -​ Cerebellum: -​ Motor control – alcohol -​ Basal Ganglia: -​ Motor loop with cortex and thalamus -​ Periaqueductal Gray (PAG) -​ Perception of pain – spine to cortex -​ Many opiate/endorphin/enkephalins receptors -​ Punishment -​ Punishing quality of pain -​ Connected to amygdala – fear -​ Limbic System: -​ Involved in control of motivations and emotions -​ Lots of drug action -​ Hypothalamus and Ventral Tegmental Area (VTA) -​ Home of pleasure centres -​ Mesolimbic Dopamine system – reinforcement system -​ Terminates in the Nucleus Accumbens -​ Drug rushes -​ Hippocampus: -​ Subtle drug effects -​ Spatial memory -​ Triggers -​ Amygdala and septum – serotonin -​ Cortex: -​ Runs on glutamate and GABA -​ Sensory integration -​ Frontal Cortex  -​ Monitors stimuli and reinforcers -​ Behavioural inhibition -​ Prefrontal cortex -​ Orbitofrontal cortex – stim reward learning -​ Dorsolateral prefrontal cortex – attention -​ Anterior cingulate – craving -​ Teratogens: -​ Thalidomide -​ Drugs that pass blood-brain cna pass placenta -​ Functional or Behavioural teratology -​ FAS, Crack, Oxytots? 1 Oct 2024 Week 5.1: Addiction -​ Sensitisation/Reverse Tolerance: -​ An effect of a drug increases with repeated administrations -​ Much less common than tolerance -​ Long lasting -​ Cross sensitisation: -​ Stress can sensitise -​ Exposure to one drug enhances the effects of another drug -​ Mesolimbic dopamine system -​ Expectancy and context -​ Context in which a drug is administered is capable of having a significant influence on the effect that the drug will have -​ Placebo effect -​ Facilitated by context -​ Expectation mechanism -​ Nocebo effect → bad trip -​ Current Diagnostic Systems: -​ 1948: WHO added a section on classification of mental disorders to the International Classification of Diseases and Health Related Problems -​ 1952: APA developed and published DSM -​ 2019: ICD-11/current system -​ 2013: DSM-5 → 5-TR in 2022 -​ Diagnostic and Statistical Manual: -​ No longer called Substance Abuse (DSM IV) -​ Replaced by Substance Use Disorder -​ Define: “behavioural, emotional or cognitive dysfunctions that involve loss of control, unexpected in their cultural context and associated with  personal distress or substantial impairment in functioning -​ Criteria 1-4: indicative of an individual's impaired control over substance use -​ Criteria 5-7: encompass social impairment associated with substance use -​ Criteria 8-9: indicate risky use of a substance -​ Criteria 10-11: pharmacological in nature -​ Course of disorder: “chronic and relapsing”,”in remission” -​ Addiction: -​ Addiction as Physical Dependence: -​ Background: -​ Withdrawal -​ Physical or psychological dependence -​ Compulsive self administration -​ Tolerance -​ Psychological Dependence: -​ Desires a drug but no ill effects in its discontinuance -​ Physical Dependence: -​ Problems with the Physical and Psychological Dependence Theories: -​ Not all develop physical dependence -​ Some will voluntarily stop taking a drug even with the presence of withdrawal symptoms -​ Does Not explain relapse -​ Psychological Dependence: -​ Invisible processes -​ Circular definition -​ What is Addiction? -​ Addiction is a behavioural syndrome where drug procurement and use seem to dominate the individual’s motivation and where the normal constraints on the individual’s behaviour are generally ineffective (self perceived “loss of control”) -​ Motivational toxicity may be a defining characteristics -​ Physical dependence is neither a necessary nor a sufficient condition -​ Motivational Toxicity:​ -​ Describes a disruption of the motivational hierarchy, this manifests as: -​ Increased motivational efficacy of the drug -​ Decreased motivational efficacy of natural rewards  -​ Motivational toxicity produces the intense motivational focusing characteristic of addiction and the apparent “enslavement” inherent in the etymology of this term -​ Modern Behavioural and Neuroscientific Explanations: -​ Background: -​ Flavour toxicosis/conditioned taste aversion -​ Animals won't do drugs if they taste bad -​ Delay is too great – P.O. -​ Only humans can become addicted → disproven -​ When it comes to choosing our goals, rationality often fails: -​ We choose our goals based on diverse factors (often lacking apparent rationality) -​ When it comes to how to obtain our goals, rationality often wins: -​ We often plan and execute out behaviour efficiently -​ Self Administration: -​ The similarity between the patterns of self admin of ethanol in a human and a rhesus monkey under continuous drug availability -​ The Arrow indicate the occurrence of withdrawal symptoms -​ -​ Humans: -​ No a great deal of difference between species but depends on type of drug -​ Drugs as positive and negative reinforcers: -​ Positive reinforcement model: -​ Positive reinforcer is any stimulus that increases the frequency of a behaviour on which it is contingent -​ Criticisms of positive reinforcement model:  -​ Paradox – how reinforcing if unpleasant? -​ Reinforcement as pleasure -​ Discounting delay for negative effects -​ Factors that alter the reinforcing value of drugs: -​ Reinforcing value of different drugs -​ Abuse potential/liability -​ Cocaine -​ Dose of drug -​ Genetic differences -​ Relief of unpleasant symptoms -​ Mixed -​ Task demands -​ Stress -​ Tail pinch, isolation, aggression exposure, unpredictable foot shock -​ Previous experience with other drugs -​ previous experience with the same drug: sensitisation -​ Physical dependence -​ Addiction cont’d: -​ The Neuroanatomy of Motivation and Reinforcement: -​ Activating and directing behaviour -​ Motivation control system of the brain: -​ Mesolimbic dopamine system -​ Ventral tegmental area (VTA) → brain's reward circuit -​ Nucleus accumbens -​ Motor loop -​ Basal ganglia -​ Thalamus – cortex -​ Learning and memory system -​ Amygdala -​ Hippocampus -​ Incentive salience -​ Disruption of Brain Control Circuits: -​ A dysfunction in information processing and integration amongst multiple brain regions -​ Circuits that regulate: -​ “reward/saliency” (nucleus accumbens and ventral tegmental area) -​ “motivation/drive” (orbitofrontal cortex and motor cortex) -​ “memory/conditioning” (amygdala and hippocampus)  -​ “Inhibitory control/executive function” (dorsolateral prefrontal cortex) -​ Treatment: -​ Treatment settings: -​ Detox and medically managed withdrawal -​ Outpatient treatment programs -​ Short-term residential treatment ~30 days -​ Long-term residential treatment ~90 days -​ Contingency Management interventions/motivational incentives -​ Rewards for “good behaviour” -​ Motivational Enhancement Therapy (MET): -​ “Why should I change?” Oct 8 2024 Week 6.1: Alcohol -​ Source of Alcohol: -​ Fermentation: -​ Sugar dissolved in water and left exposed to the air -​ Yeasts – microorganisms come and consume sugar and multiply, then convert sugar into ethanol and carbon dioxide -​ Ethanol and carbon dioxide (bubbly) -​ Vapour steams and then condenses into alcoholic liquid -​ Then redistilled into really high alcohol concentration -​ 10-15% -​ Distillation: -​ 40-50% -​ Alcohol lower boiling point vs water -​ Measurement of Alcohol: -​ In the U.S. a proof spirit (100 proof) is containing 50 percent alcohol by volume -​ Thus the U.S. proof number is twice the percentage of alcohol by volume → complicated -​ Canada and other countries – alcohol by volume/ABV -​ Origin and History: -​ Use from before recorded history -​ Most cultures drink alcohol regularly -​ The first alcohol that humans consumed was probably in the form of fermented honey or fruit -​ Deliberate fermentation probably began with the development of agriculture  -​ Book of the Dead (abt 3000 BC) → Beer -​ Distillation: China 3000 BC -​ Greeks and Romans (lead poisoning) -​ Fall of the Roman Empire -​ Early British and American Experience: -​ Usquebaugh = whiskey 1500s -​ An Inquiry into the Effects of Ardent Spirits (1785) -​ American Prohibition: -​ Temperance movement -​ Advocated for alcohol ban -​ Was successful -​ Eighteenth Amendment 1917 – Prohibition Enacted -​ Twenty-first amendment 1933 – Prohibition Repealed -​ Yearly alcohol consumption -​ Current U.S Levels peaked in 1979 -​ Slowed in the 1990s -​ Mothers against driving -​ Other petitions, taxes, warning labels -​ Measuring alcohol levels: -​ Blood Alcohol Level (BAL) -​ Concentration of alcohol in whole blood -​ Metric measurements and percent -​ BAL = milligrams (mg) of the alcohol per 100 millilitres (ml) of blood -​ Conversion = moving the decimal point three places -​ BAL of 80 mg per 100 ml or 80 mg/dl is the same as 0.08% -​ Excreted from lungs at known rate (breathalyser) -​ ROA and Pharmacokinetics: -​ Theoretical time course for BALa after taking a single drink -​ A: Absorption phase -​ B&C: Plateau phase -​ D: Excretion Phase -​ Age, sex, ethnicity, history of drinking, metabolism, weight -​ -​ Absorption: -​ Orally: absorption in digestive tract -​ First pass metabolism in stomach -​ Faster on empty stomach – direct to small intestine -​ Gender difference in first pass metabolism -​ Females – less alcohol dehydrogenase -​ Concentration contributes to speed of absorption -​ 40% most rapid -​ Higher slows stomach -​ Diffusion rates increase with rising alcohol content -​ Carbonation -​ Alcohol: Differences -​ Less alcohol for women because less alcohol dehydrogenase -​ More body fat percentage, feel more -​ Crosses blood-brain and placental barrier (baby) -​ Excretion: -​ Chronic alcohol, users tend to have lower levels of first-pass metabolism (lower alcohol dehydrogenase) -​ Small percentage eliminated -​ Breath, sweat, tears, urine, faeces -​ 90% metabolised by the liver -​ Metabolism of alcohol: -​ Rate-limiting step (1st step) – dependent on alcohol dehydrogenase -​ Acetaldehyde -​ Converted into acetyl-coenzyme (2nd step) -​ Energy, water, and carbon dioxide -​ Individual differences:​ -​ Drinking experience, and food affect metabolism -​ Microsomal ethanol oxidising system (MEOS) -​ Alternate metabolising system – hyperactive among heavy drinkers -​ Barbiturates -​ Neuropharmacology: -​ Complex and mysterious -​ Non specific receptor sites -​ May interact with an alcohol sensitive area on the receptor -​ Enter and block the ion channels -​ Glutamate – NMDA receptor inhibition -​ Upregulation – hypersensitisation – seizures/withdrawal -​ GABA-receptor excitation – enhanced inhibition -​ Ultimately downregulation  -​ Alcohol Antagonists -​ Naltrexone ​ -​ blocks opioid receptors in the brain and makes it not feel good -​ Caffeine -​ Effects of alcohol: -​ Effects on the body: -​ Dilation of blood vessels in the skin -​ Makes skin feel warm -​ Loss of body water (frequent urination) -​ Effects on sleep: -​ Induces sleep -​ Decreases time it takes to go to sleep -​ Depresses REM sleep -​ Rebound -​ Cessation leads to disturbance in sleep patterns – long term -​ Effects on Behaviour: -​ Low dose = stimulation -​ > talking and higher pitch -​ Excitement and elation -​ High dose = sedation -​ Anger and depression -​ Perception -​ < flicker fusion -​ < smell, taste and pain -​ Performance -​ Reaction time – 10% at low doses -​ Inner ear – the spins -​ Expectancy and incentives -​ Memory and blackouts -​ Affect both storage and retrieval of information -​ Fragmentary blackout (grayout) -​ Retrieval -​ En bloc blackouts -​ Effects on driving -​ Higher speeds, increase in collisions -​ Police can issue a 3-, 7-, or 30- or 90-day prohibition if they find that alcohol has affected your ability to drive -​.05 = warning 3 day suspension -​.08 = 90 day suspension -​ The relationships between BAL and the relative risk of being involved in a traffic accident for people of different age groups -​ Effects on nonhumans: -​ Do rodents like drinking -​ Guinea pigs can metabolise alcohol really well -​ Conditioned behaviour -​ Biphasic → @ low dose < @ high dose -​ Punishment – reemergence of punishment suppressed -​ Discriminative stimulus properties: -​ Alcohol vs saline -​ Easily -​ barbiturates/benzo -​ Yes and no -​ Tolerance: -​ Acute tolerance -​ Across the BAL curve -​ Chronic tolerance -​ dose increase 30-50% within weeks -​ Metabolic tolerance -​ Dehydrogenase -​ Behavioural tolerance -​ Practice -​ Functional alcoholic -​ Withdrawal: -​ early/minor symptoms: -​ 8-2 hours starts – last 48 hours -​ agitation , tremors, muscle cramps, vomiting, nausea, sweating, vivid dreaming, and irregular heartbeats -​ late/major: -​ 2 days onset – 7-10 days -​ Delirium tremens (DTs) -​ Hallucinations and seizures -​ Morbidity -​ Harmful Effects: -​ Alcohol poisoning: -​ Respiratory failure -​ TI 3.5 -​ Vomit for safety: -​ Hangover -​ Alcohol induced behaviour -​ The liver: cirrhosis -​ The nervous system: korsakoff’s psychosis – thiamin deficiency Wernicke’s disease -​ Cancer: mouth, throat, and liver, acetaldehyde is a carcinogen -​ Reproduction:  -​ Males – shrinking of the testicles, impotence, and loss of sexual interest -​ Females: menstrual dysfunctions -​ FAS -​ Heart disease: alcoholic cardiomyopathy -​ Alcohol and Cannabis: -​ Co use of alcohol and cannabis resulted in less harms and protected from feelings of regret following heavy episodic drinking Oct 10 2024 Week 6.2: Addictions Treatment – Past, present, and future -​ Seeking Treatment: -​ Substance use exists on a continuum -​ Behavioural Addictions: -​ Gambling Pornogrpahy, shopping… -​ Signs of Problems: -​ Increased involvement with substances -​ Continued use despite negative consequences -​ DUIs -​ Behaviour changes… impulsivity -​ Spending less time on things they care about -​ Impatience, quick to anger and annoyance -​ Impulsivity as a risk factor and an effect -​ Craving, tolerance, and withdrawal -​ Even behavioural addictions can produce a withdrawal effect -​ Shifting values towards drug use -​ Functional impairments -​ Concurrent Disorders: -​ Define: mental disorder + use disorder +/- substance-induced disorders -​ Issues has been that institutions like to separate all of these “get help for addiction first and then come to mental health treatment” and vice versa -​ More than 50% of people with addiction have a mental illness -​ 15-20% of people with a mental illness also have an addiction -​ About 13,000 people in BC have concurrent disorders -​ Higher levels of unmet need and low satisfaction with systems of care -​ Polysubstances: multiple substances to manage mental health system -​ Risk Factors for Concurrent Disorders: -​ Earlier age of first drug use, or earlier age of mental illness onset  -​ High impulsivity, family history, poverty, unstable housing, social isolation, problems with work or school -​ ACEs: -​ Abuse – emotional physical, sexual -​ Neglect – emotional, physical -​ Household problems – separation/divorce, domestic violence, drug abuse, crime, mental illness -​ Most people with substance use disorders have five of these^^ -​ What I commonly see: -​ Mood and Anxiety: -​ Low mood, worry, sleep issues -​ Rigidity: -​ Perfectionism, inflexible self-image, burnout -​ ADHD: -​ Hyperactivity, disorganised, impulsivity -​ PTSD: -​ Nightmares, hyperarousal, dissociation -​ Psychosis and Cannabis: -​ Stronger in males than females -​ ~45,000 cases of schizophrenia in 6.9m people age 16+ -​ People who have a genetic risk for psychosis could be triggered -​ Genetic risk factors the more likely you are to develop this substance use disorder → one of the more overt -​ Progerminal period: before having delusions, there's a period where someone can become socially withdrawn, depressed → if screened could be stopped -​ Psychosis and Substance use: -​ Psychosis can last months or years past substance use -​ “Organic” psychosis or drug induced? -​ Chicken and the egg -​ Would this person have developed this severe mental illness had they not been using substances -​ Other drugs: -​ Methamphetamine -​ Alcohol -​ Ketamine -​ Serotonergic psychedelics -​ A History of Addictions Treatment: -​ 10,000 B.C. → first recorded use of beer and wine; cannabis tobacco, opium, cocaine, and entheogenic plants used for thousands of years -​ Indigenous “Recover Circles” abstinence-based healing circles  -​ Middle Ages → moderated alcohol use popular, dependence viewed as moral issue requiring religious intervention and or punishment -​ 1700s, 1800s → Pinel, Rush and Kraepelin viewed alcoholism as medical condition instead of moral failing -​ 1860s – 1890s → alcoholics treated in “inebriate homes” and asylums -​ 1920s → Carl Jung and William James both believed only a profound spiritual experience can cure addiction -​ 1930s → first addiction treatment facility in US for jazz musicians addicted to heroin -​ 1934 → Bill Wilson has spiritual experience form the “Towns-Lambert Cure” in a private hospital (includes psychotropic cocktai;l of hypnotics and hallucinogens) -​ Next morning, Carl Jung’s patient (founder of Oxford Group in NYC) bring Bill The Varieties of Religious Experience; inspired AA program of 12 steps -​ 1950s → AMA defines alcoholism as a disease, increased resources for treatments -​ 1970s → Controlled Substances Act passed -​ 1987 → AMA defines all drug addiction as a brain disease -​ Problems with the Disease Model: -​ Fails to account for neuroplasticity of reward systems -​ “Your brain is broken and you are destined for drug addiction” -​ There is no “addiction gene” -​ Ignores personal responsibility and choice -​ Poor explanation for behavioural addictions -​ Most people have “spontaneous remission” -​ Reinforces black and white thinking -​ Reinforces the “allergy” myth -​ Criticisms of AA: -​ Strong religious tone, major barriers to treatment -​ Black and white thinking, assumption that people are either “addicts/alcoholics” or “normies”; you either have the disease or you don't -​ Lifelong commitment to sobriety or else…? -​ Bias towards personal experience over professional training -​ Dangers of “anonymity” -​ 12 step culture, identity, false beliefs -​ Post-treatment relapse rates ~60% in year after discharge -​ Recent development: ​ -​ Moderation as a goal for SUD treatment -​ Harm reduction increases -​ Naloxone overdose response  -​ Decriminalisation of personal use -​ Prescribed alternative supply -​ Integrated Model of Addiction: -​ Akrasia: a state of mind where a person acts against their better judgement through incompetence of will -​ Cookie -​ To use or not to use: -​ Why am I using it? – motives -​ How will it make me feel? – expectancies -​ What could go wrong? – risk assessment -​ How much does it cost? – demand -​ Is this the setting I normally use in? – environmental cues -​ The Addictive Personality: -​ Impulsive personality traits are transdiagnostic marker common to SUD and other disorders -​ Lack of premeditation is strongest predictor of relapse in SUD -​ Positive urgency, negative urgency, lack of premeditation, lack of perseverance, sensation seeking -​ Biobehavioral model of addiction: -​ Reduced reward response to non-drug cues; sensitised response for drug related cues -​ Hijacking of dopaminergic and endorphin pathways -​ Weaker functional connectivity striatum → OFC linked to increased behavioural impulsivity -​ Motivational Enhancement Therapy: -​ A collaborative approach to substance use assessment and treatment -​ Exploring and resolving ambivalence around substance use -​ Personalised feedback on drug use -​ Values-centred -​ Compatible with existing treatment -​ Brief intervention -​ Therapeutic Processes: 1.​From disconnection to connection -​ Disconnected from relationships, place on this earth -​ Cause feelings of intense connection to all things 2.​From experiential avoidance to acceptance -​ Something feels bad I'm going to avoid it -​ Repairing relationships: I'm not happy with it but I am going to accept that it is in that state -​ Now I can make steps towards reparation -​ Psychedelic Assisted Therapy: -​ Preparation → Dosing → Integration  -​ Ketamine → pain depression trauma and anxiety but still experimental -​ Could help treat most disorders -​ Psilocybin: -​ 3 prep sessions -​ During dosing session there up to eight hours -​ May want to talk a bit but instead go in and access innate ability to heal… the secrets are within us -​ And then a few integration sessions -​ MDMA is similar but there is therapy done during it -​ Psilocybin for substance use: -​ Synthesised psilocybin safe and reliable -​ 10 clinical trials with 379 patients using psilocybin to treat mental disorders -​ 2 pilot trials for addiction: alcohol dependence and smoking cessation -​ For alcohol dependence: -​ 2 doses in 12 week MET intervention -​ Mystical experiences were associated with greater reductions in drinking -​ Importance of meaningful experiences -​ For smoking cessation: -​ 3 doses in a 15 week CBT intervention -​ 80% remained smoke free at 6 months; 67% at 12 months -​ 13/15 participants rated psilocybin as “top 5 most spiritually significant experience of their lives” Oct 15 2024 Week 7.1: Sedatives: -​ Anxiolytics and Sedative Hypnotics: -​ Tranquilisers or anxiolytic -​ Drugs that are used therapeutically to treat agitation or anxiety -​ Sedative hypnotic: -​ Drugs used to sedate and aid in sleep -​ Same mechanisms – differences in onset and duration -​ GABA facilitation -​ How to calm people down: -​ A brief history: -​ Prior to 1864: alcohol, bromides, chloral hydrate, opium -​ Barbiturates: 1864 -​ 1000s -​ Treatment of anxiety and insomnia  -​ Phenobarbital: prevents seizures -​ Decline in legal supply = reduced illicit supply -​ Benzos: 1950s -​ Chlordiazepoxide (Librium; 19578) -​ From random investigation -​ Diazepam (Valium 1963), Lorazepam/Ativan -​ Flunitrazepam (Rohypnol; 1990s) – roofies -​ Date rape drug -​ Methaqualone (Quaaludes;1960s) -​ Anxiolytics and Sedative Hypnotics: cont’d -​ Route of Administration and Absorption: -​ Weak acids – low PKA 3.5-5 -​ Readily absorbed after parenteral and oral administration -​ Range in lipid solubility – range in onset -​ diazepam/valium – 30-60 min peak -​ Individual differences in absorption (up to 20X) -​ Beer – if two people drink beer and one has normal and the other absorbs the same amount of beer at a rate of 20x -​ Absorption form the digestive systems may be greatly increased by the drinking of alcohol -​ 2x w/small dose -​ Distribution and Excretion: -​ Distribution and duration determined by lipid solubility: -​ Brain to fat – then slow half life and excretion -​ Lipophilic = feel it faster but effects are shorter -​ Fast acting = short duration -​ Metabolites sometimes active - (older BZs) -​ Metabolism slowed and effects prolonged by alcohol -​ Neurophysiology: -​ GABA – all over CNS – inhibitory tone -​ Opens ion channels – permits flow – increases stability -​ + stability = less firing = inhibition -​ Barbs and BZs affect GABAa and GABAb receptors -​ Specific receptor sites on GABA-chloride ionophore complex -​ GABA neurotransmitter made more effective -​ Benzos act as positive GABA modulators -​ Endogenous GABA sets upper limit -​ Barbs – at high doses can open the gates independently -​ No upper limit = fatal OD  -​ Several types of GABAa receptors -​ Different effects -​ Sedative vs anxiolytic -​ Target for development of new BZs > greater specificity -​ Endogenous Substances -​ Endozepines -​ Increases receptivity post stress -​ Still looking -​ Effects on the Body: -​ Few effects outside the CNS -​ Muscle relaxant properties -​ From brain? -​ MS and Parkinson’s -​ Anticonvulsants -​ Increase appetite -​ Weight gain – side effect -​ Effects on sleep: -​ Effective in treating insomnia -​ Decrease latency, wakefulness, increase total time -​ Decrease time spent in REM -​ Rebound with habitual use and discontinuation -​ Hard to sleep without it -​ Effects on behaviour and performance of humans: -​ Subjective effects -​ Euphoria and fatigue -​ More liking with abusers of other substances -​ Effects on performance: -​ Flicker fusion -​ Severe anterograde amnesia -​ Explicit memory vs implicit memory -​ Cues? -​ Sedation, attention, and psychomotor effects -​ Poor digit symbol and RT -​ Long lasting – poor insight -​ Residual effects -​ Morning after -​ Effects on driving -​ Alone and interactions with alcohol -​ Effects on behaviour of nonhumans: -​ Unconditioned behaviour of nonhumans -​ Taming -​ Reduced defensive aggression  -​ Vs. attack -​ Conditioned behaviour -​ Avoidance vs escape -​ Increase in reemergence of punished behaviour -​ Discriminative stimulus properties: -​ Benzodiazepines vs. saline -​ Generalise to alcohol and barb -​ Also discriminate -​ Tolerance: -​ Acute tolerance – limited behavioural -​ Chronic tolerance -​ Pharmacodynamic – less GABA modulation -​ Behavioural -​ Anxiolytic -​ Cross-tolerance -​ Alcohol -​ Barb -​ Withdrawal: -​ Similar mechanisms barb and BZ -​ Historically underplayed by medical establishment -​ Sedative-hypnotic type -​ 1 months high dose = 10 days -​ Tremors, delirium, cramps and convulsions -​ Low-dose Withdrawal: -​ 6 months = 2 weeks - 1 year? -​ 15-44% of users -​ anxiety , panic, irregular heartbeat, increased blood pressure, impairment of memory, feelings of unreality, muscle spasm and a sensitivity to light and sounds -​ Two types of withdrawal symptoms that may be seen after use of the benzodiazepines -​ Can have both types -​ Old symptoms return -​ Self Administration in humans: -​ Laboratory studies: -​ Choice experiments -​ Not chosen over placebo even among high anxious -​ Alcohol users choose over placebo -​ Self-administration: -​ Sedative abusers would work for high does - barb > bz -​ Outside the Laboratory -​ Iatrogenic Use – physician causes  -​ Most with anxiety and health problems -​ Over and underuse -​ Street use -​ Most often taken with another drug – alcohol or opiates -​ Self-Administration in nonhumans: -​ BZs < Barb -​ Short Acting > slow -​ Sensitised by prior exposure -​ Alc and barbs -​ Harmful effects: -​ Reproduction: -​ Teratogen in rats … withdrawal in newborns -​ Overdose: -​ At worst 15,000 barb ODs -​ Suicide -​ Overdose of benzodiazepines are not usually fatal -​ Mixture of benzos and alcohol or opioids are often fatal -​ Treatment: -​ Withdrawal can be severe with medical attention required -​ Detox → Weening 22 Oct 2024 Week 8.1: Stimulants -​ Liam Payne: -​ “Pink Cocaine” sometimes called “2C,” “Tuci,” “Tusi” -​ 2 ketamine: 1 MDMA with food colouring -​ Can contain many other drugs (Viagra, LSD, meth…) -​ It is NOT COCAINE… and not to be confused with 2CB -​ Psychomotor stimulants: -​ Sources: -​ Naturally occurring: -​ Ephedrine (Ephedra, Mah Huang) -​ Cathinone (khat) -​ Methcathinone (cat) -​ Cocaine -​ Erythroxylum coca -​ Synthetics: -​ Amphetamines: -​ D (dexedrine and L (levo amphet) -​ Mixed (dl – Adderall/benzedrine – bennies) -​ Methamphetamine (crystal, ice, crystal meth)  -​ Methylphenidate (Ritalin → cough meds) -​ Cocaine: -​ Pre-columbian (2500 B.C.) -​ Included in creation myths -​ Sacred to Incas -​ Erythroxylum coca -​ Isolated by Albert Neiman (1860) -​ Late 1800s -​ Freud -​ Sherlock Holmes -​ First local anaesthetic -​ Added to various beverages -​ Coca-cola still contains inert coca leaves -​ Still the largest importer of cocaine -​ Harrison Narcotic Act of 1914 -​ Along with morphine and opium -​ History: -​ Amphetamines -​ Stimulates our nervous system -​ Dilates our airways -​ Degrades when exposed to light or air -​ Can be taken orally because our gut enzymes destroy it very quickly -​ Must be injected -​ And must take multiple -​ Ephedrine used in china for 5,000 years – ma huang -​ Similar to Epinephrine -​ More stable > medical use – asthma -​ Amphetamine synthesised in 1887 -​ Use as ephedrine substitute – 1927 -​ Medical use sanctioned by AMA – 1937 -​ By 1943 used for weight reduction, antidepressant, stimulant, extended periods of alertness -​ Methylphenidate developed as competitor -​ Current use – narcolepsy and hyperactivity -​ Cathinone – Khat = synthetic mephedrone (bath salts?) -​ ROA and Absorption: -​ Amphetamines: -​ Absorbed poorly from digestive system -​ More potent when administered by injection or inhalation -​ Rush vs consistent release -​ Sleep disorders  -​ PKA of amphetamines are quite high, when they enter into digestive system → acidic → amphetamines become ionised and its then hard to get through the lipid digestive tract -​ Cocaine: -​ Coca leaves chewed with lime from wood ash or sea shells -​ Inhaled as salt -​ Smoking -​ Has to be converted into a freebase -​ Crack is cocaine with sodium bicarbonate/baking soda -​ Free base from salt and remove ionic charge which increases the drugs’ lipid solubility -​ Indigenous peoples usage: -​ High PKA -​ They realised that if they took it with ash or crushed shells, the cocaine would absorb more readily, ionised cocaine and would absorb better through the mouth than stomach -​ Peak within 25 minutes -​ Crack: -​ Cocaine HCL mixed with baking soda -​ Less expensive – rapid onset and short lived effects -​ You lose 30% of the drug to smoke -​ Snorting you lose less -​ Distribution: -​ Cross the blood-brain barrier and are concentrated in the spleen, kidneys, and brain -​ Excretion: -​ Amphetamine -​ Excretion in urine, sweat and saliva -​ Half-life between 16-34 hours -​ Active metabolites -​ Cocaine -​ Excreted much faster than amphetamines -​ Half-life of about 40 minutes -​ Depending on urine ph, it will dictate how amphetamine will leave system, -​ As your urine becomes more basic more of the drug is being absorbed by the liver -​ Psychomotor Stimulants: -​ Multiple effect on Monoamine Synapses -​ Act on vesicular monoamine transporters (VMAT) -​ Amphetamines increase monoamines in the synaptic cleft that leads to effects  -​ Large proteins move across the membrane and transport monoamines in and out -​ Dopamine, serotonin, norepinephrine each have their own transporter -​ Amphetamines -​ Leaking of neurotransmitter released in response to action potential -​ Block reuptake (both amphetamine and cocaine) -​ Cocaine is only a reuptake blocker -​ Up to 77% of DA transporters blocked (47% for subjective effects) -​ Nigro-stritial and mesolimbic -​ Most effects due to dopamine in the nucleus accumbens -​ Cocaine also blocks ion channels in membranes -​ Inhibits firing – local anaesthetic – -​ Effects of Amphetamines: -​ Effects on body: -​ D (adderall) and L -​ Increase in heart rate and blood pressure -​ Vasodilation and Bronchodilation -​ Headaches, dry mouth, stomach disturbances, weight loss -​ Meth -​ >CNS and Abuse -​ Effects on sleep: -​ Prevent sleep -​ Insomnia -​ Effects on Behaviour and Performance: -​ Subjective Effects – IV cocaine and amphetamine very similar -​ euphoria , well-being and energy/exhilaration -​ Acute tolerance -​ Cocaine shorter acting – 20-30 minutes rush -​ Comedown -​ Correlated cortical activation -​ Stereotyped behaviours: punding → repetitive cleaning behaviours -​ Amphetamine psychosis: ​ -​ Formication -​ Paranoid schizophrenia -​ Violence -​ Sensory effects: -​ Increase in visual acuity -​ Slight improvement in auditory and visual flicker fusion -​ Effects on performance  -​WWII -​Counteract fatigue -​>vigilance and attention -​Overlearned​clock text -​Athletic performance bronchodilators -​ Banned by most national sports federations -​ Effects on the Behaviour of nonhumans: -​ Unconditioned behaviour -​ `increase spontaneous locomotor sniffling and other stereotyped behaviours high doses -​ Automutilation -​ Decrease food and water consumption -​ Psychomotor Stimulants: -​ Dissociation and Drug State Discrimination -​ Animals trained under the influence of amphetamine cannot completely remember what they learned when the amphetamine has worn off -​ Discriminate from saline -​ Generalise cocaine and amphetamine -​ Tolerance -​ Acute tolerance → coke out -​ Chronic tolerance and sensitization -​ Appetite, heat, blood pressure, effects become tolerated with repeated administration -​ Sensitisation – stereotyped behaviours and psychosis -​ Withdrawal: -​ Not associated with a severe or medically serious withdrawal -​ Depression, insomnia, -​ Guilt birds -​ Monoamine related long-term depression -​ Like clinical depression -​ Suicidal ideation -​ Decision making -​ Lower dorsolateral prefrontal activation up to 1 year abstinent -​ Harmful effects: -​ Direct Effects: -​ Treat hyperactivity in children (methylphenidate) -​ This sometimes causes a reduction in growth velocity -​ Concerns re: diagnosis -​ Non-specific effects  -​ Cocaine effects: -​ Mild jaundice/liver disease -​ Inflammation and ulceration of the mucous membrane in the nose -​ Expensive -​ Amphetamine Effects: -​ Restlessness, excessive talking, confusion and dizziness -​ Paranoid psychotic behaviour (chronic use) -​ Due to lack of sleep -​ Increased blood pressure, stroke -​ Depression, suicidal tendencies, lethargy and sleep disturbance occur with cessation of use -​ Neurotoxic effect on the brain -​ Indirect Effects -​ IV use -​ Hepatitis -​ HIV/AIDS -​ Violence -​ High death rate – similar to those with problematic alcohol and opioid use (?) -​ Contamination -​ Reproduction: -​ Enhance sexual activity -​ Chemsex -​ High risk sex -​ Chronic use leads to disruption in sexual activity -​ Overdose: -​ Cocaine -​ Large doses -​ Muscle weakness and respiratory depression -​ Lethality depends on route of administration -​ Cardio events -​ Caine reaction -​ Initial excitement followed by severe headache, nausea, vomiting and severe convulsions -​ Followed by loss of consciousness, respiratory depression and cardiac failure resulting in death -​ Can treat overdose with diazepam -​ Treatment: -​ Detoxification  -​ Positive reinforcement -​ Counselling -​ Contingency management -​ Priming and sensitisation increase relapse risk -​ Drugs -​ Antidepressants -​ Modafinil -​ Substitution therapies -​ Methylphenidate → not that successful in cocaine abusers -​ Psychomotor Stimulants: -​ Based on our considerations, we call for a presumption that mentally competent adults should be able to engage in cognitive enhancement using drugs. -​ We call for an evidence-based approach to the evaluation of the risks and benefits of cognitive enhancement. -​ We call for enforceable policies concerning the use of cognitive-enhancing drugs to support fairness, protect individuals from coercion and minimise enhancement-related socioeconomic disparities. -​ We call for a programme of research into the use and impacts of cognitive-enhancing drugs by healthy individuals. -​ We call for physicians, educators, regulators and others to collaborate in developing policies that address the use of cognitive-enhancing drugs by healthy individuals. -​ We call for information to be broadly disseminated concerning the risks, benefits and alternatives to pharmaceutical cognitive enhancement. -​ We call for careful and limited legislative action to channel cognitive-enhancement technologies into useful paths. Oct 24 2024 Week 8.2: Caffeine and the Methylxanthines -​ Xanthine stimulants or methylxanthines: -​ Occur naturally -​ 1st isolated from coffee in 1820 -​ Vasoconstrictor -​ Coffee: -​ Arabica and Robusta  -​ Seed of coffee tree berry -​ 80% of the world -​ Second most traded product in the world -​ Tea: -​ Made from leaves of Camellia Sinensis -​ Black (fermented/oxidised) -​ Oolong/white (semi fermented) -​ Green (unfermented) -​ 12-14% of caffeine -​ Scented with flower petals -​ Jasmine -​ Contains caffeine more than coffee beans but… -​ Theophylline and Theobromine -​ Drug amount in plant will be affected by where and how its grown and how it's harvested and brewed -​ Cocoa: -​ Cacao tree (seeds) -​ Native to tropical amazon forest -​ Cacao plant versus cocoa -​ Caffeine (2.5%) and theobromine -​ Other natural sources of methylxanthines: -​ Ilex plant -​ Holly -​ Amazon region -​ Yerba Mate 1% caffeine -​ Guarana -​ Amazon -​ 2-6% caffeine -​ Most potent natural source -​ Cola -​ Southern Nigeria -​ Nut can be chewed -​ Food: -​ Cola beverages -​ Pudding mixes -​ Baked goods -​ Dairy desserts and candy -​ Medicines: -​ Headache -​ Weight control aids -​ Allergy relief compounds -​ Stimulants -​ Asthma medications -​ History: -​ Coffee -​ Ethiopia (12th - 15th centuries) -​ Spread to Europe -​ Long association with politics and intellect -​ Tea -​ China – 780 AD Tea Classic → tea propaganda -​ 1600s to Europe -​ Cocoa -​ Mayas, Aztec, Incas (pre-columbian) -​ Theobroma -​ Spain in 1520 – secret for a century -​ 1st chocolate factory in England 1728 -​ Route of Administration: -​ Orally -​ Rectal suppository -​ Intramuscular or intravenous -​ Absorption: -​ Lipid soluble -​ Digestive system -​ Most from intestines -​ Peak 30-60 minutes -​ Distribution: -​ Caffeine crosses the blood brain and placental barriers -​ Excretion: -​ 98% metabolised -​ Half life (2½ to 4½ hours) -​ Longer for theophylline and theobromine -​ Caffeine Metabolism: -​ Individual differences – genetic – enzymatic -​ Slowed by alcohol -​ Smokers eliminate caffeine twice as fast as nonsmokers -​ Elimination affected by female hormones -​ Infants cannot metabolise caffeine -​ Neurophysiology: -​ Adenosine receptor blocker -​ Adenosine is inhibitory neuromodulator -​ Reduces spontaneous firing rate across brain -​ Adenosine acts on GABA neurons to inhibit dopamine release -​ Methylxanthines block these effects -​ Removal of GABAergic inhibition increases dopamine release -​ Also epinephrine and other catecholamines  -​ High doses – block benzodiazepines receptors -​ Anxiety -​ Effects on the body: -​ Stimulates sympathetic nervous system -​ Epinephrine from adrenal gland -​ Bronchial dilation – asthma tx -​ Vasoconstrictor in brain – headache tx -​ Effects on Human Performance and Behaviour -​ Perception vs performance -​ Effects on Sleep: -​ Insomnia, wake up more easily, tolerance -​ Tolerance: -​ Increase generation of adenosine receptors -​ Subjective effects tolerated on 4 days -​ Withdrawal: -​ Can develop in a couple weeks -​ Headache -​ Drowsiness -​ Decreased energy -​ 12-28 hour onset -​ 2-9 days -​ Overlooked reason for cold-like sx – particularly with schedule change (holidays) -​ Harmful effects: -​ Reproduction -​ Reduces blood flow to the foetus -​ Lowers birth rate -​ Breast milk -​ Cardiac disease -​ Increase in blood pressure -​ Debatable whether it causes heart disease -​ Anxiety disorders -​ Panic d/o -​ Caffeine-induced Anxiety disorder: -​ Diagnostic criteria: 1.​Panic attacks or anxiety is predominant in the clinical picture 2.​There is evidence from the history, physical examination or laboratory findings of both (1) and (2): a.​The symptoms in criterion A developed during or soon after substance intoxication or withdrawal or after exposure to or withdrawal from a medication  b.​The involved substance/medication is capable of producing the symptoms in Criterion A -​ Lethal: -​ Lethal dose is between 3 and 8 grams (30-80 cups of coffee) -​ Convulsions and respiratory collapse 29 Oct 2024 Week 9.1: Nicotine -​ Tobacco and Nicotine: -​ Preparations -​ Nicotiana tabacum (6%) -​ Cured and prepared -​ Leaves dried and then ground -​ Cigars, cigarettes, pipe tobacco, chewing tobacco, moist snuff -​ N. Rustica (9%) -​ Traditional use -​ Original to the Americas: -​ tobacco/tabacco = 2-pronged tube used to make snuff -​ Speculated that tobacco has been cultivated in the Americas since 6,000 BC -​ Smańx^w or wild tobacco is a culturally important plant for the Sylix People -​ Given to Columbus first landfall 1492 -​ Columbus and his crew were the first Europeans to see tobacco smoking -​ “Drink smoke” -​ Earliest known illustration of smoking was a stone carving from a Mayan temple -​ Post Colombian: -​ Jean Nicot French Ambassador to Portugal -​ Medical usefulness -​ Name given to plant -​ Ent tobacco seeds from Portugal to Paris in 1550 -​ English late 16th Century -​ 1604 King James “Counterblaste to tobacco” early PSA -​ Colonial export -​ Cigarettes 1840s -​ Surgeon General’s Report 1964 -​ Globally about ½ men smoke compared to 12% women -​ 15,000,000,000 cigarettes a day -​ Today – decline in industrialised nations and increase in developing nations -​ Route of Administration: -​ Never consumed in pure form – poisonous -​ Orally: -​ Not readily absorbed from digestive system -​ Poisonous if eaten -​ Sniffed: -​ Nicotine absorbed through mucous membranes of nasal cavity -​ Patch, nicotine inhaler/vape -​ Smoked: -​ 90% of inhaled nicotine absorbed through mucous membranes of lungs -​ 1.5-2.6mg of nicotine in 10-15 puffs -​ Lungs direct to heart – quick -​ No dissipation in blood – bolus to brain -​ Nicotine in cigar and pipe smoke absorbed through mouth -​ Less acidic -​ Slowly – no bolus -​ -​ Distribution: -​ Depends on the route of administration and the time after administration -​ Smoking style = wide variation 10x -​ Nicotine crosses most barriers including the placenta and may be found in the milk of nursing women -​ Excretion: -​ Kidneys -​ Liver – faster in smokers, genetic differences, metabolic defect -​ Neurophysiological Effects: -​ Two types of cholinergic receptor sites -​ Nicotinic -​ Stimulated by nicotine -​ Blocked by Curare – neuromuscular -​ Muscarinic -​ Stimulated by Muscarine -​ Mechanism of Action:  -​ Occupies and activates nicotinic cholinergic sites -​ Excitatory postsynaptic -​ Neuromodulator pre-synaptic -​ Stages – basal, active, and desensitised (closed) -​ Return to basal – hours -​ Upregulations -​ >nicotinic acetylcholinergic receptors -​ = withdrawal effects -​ Effects: -​ Moderated by multiple systems and biphasic effects -​ Peripheral Nervous System -​ Neuromuscular junction -​ Muscle tremors -​ Constriction of blood vessels in the skin -​ Cold touch, ageing, reduced blushing -​ Inhibits stomach secretions -​ Laxative -​ Nausea -​ Tolerance -​ CNS -​ Complex and mysterious -​ Alertness -​ Epinephrine -​ Euphoria -​ Norepinephrine and dopamine -​ Dopamine in nucleus accumbens -​ Serotonin -​ Antidepressant? -​ Sleep: -​ Reduce total sleep time, increase sleep latency -​ Withdrawal disrupts sleep -​ >REM – feel less refreshed next day -​ Subjective effects: -​ Acute effects: -​ Pleasurable -​ In smokers rush last around 10 seconds -​ Paradox: -​ Nicotine causes arousal and a release of epinephrine yet most people say it relaxes them -​ Tactile? -​ Relief from withdrawal? -​ Dose-response differences → controlled by inhalation -​ Subjective arousal – relative to stress -​ Chronic effects:  -​ Control stress? Improve mood? -​ Negative mood with quitting followed by overall increase -​ Smokers generally lower well-being -​ Effects on performance: -​ Conflicting results: -​ Smokers vs non -​ Deprivation related impairment -​ Dorsolateral-prefrontal cortex → activation on cog tasks -​ Withdrawal -​ Improved performance on: -​ Fine motor -​ Monotonous tasks -​ Orienting -​ Episodic memory -​ Reaction time -​ Withdrawal Symptoms: -​ Psychologically stressful -​ Vs heroin -​ Sme physical dependence -​ Decreased heart rate, increased eating, inability to concentrate, difficulty sleeping, anxiety, anger, aggression, depression, drowsiness, lightheadedness, headaches, dizziness, tremors, and nausea -​ Over within a month -​ Not induced by nicotine blockers -​ Reduced by denicotinized cigarette -​ Unaffected by previous rate or duration of use -​ Factors that create the addiction: -​ 10-15% current alcohol drinkers are considered problem drinkers but >75% of smokers consider themselves nicotine addicts -​ Rapid and frequent reinforcement (200 times a pack) -​ Rapid metabolism (clearance allows frequent and repeated use) plus rapid onset of withdrawal -​ Complex direct pharmacological effects -​ Smoking conditioned to other activities (eating, drinking, driving) -​ Factors Promoting Addiction: -​ No performance impairment; might even be improvement in alertness, reaction time -​ Relatively inexpensive (?) -​ No equipment other than match -​ Readily available (?) -​ Portable easy to store  -​ Legal for 18 and up -​ Self administration in humans: -​ Constant blood level theory: -​ Titration through smoking style -​ Topology across a cigarette -​ Nicotine Bolus Theory: -​ Sudden puff – positive reinforcer -​ Like IV heroin -​ Reinforcement increased by rapid high concentration -​ Accounts for popularity of smoking -​ Smoking behaviour in humans: -​ Early historical use – infrequent and high doses – ceremonial -​ Tobacco chippers -​ Occasional use without dependence -​ Frequently burned and inhaled through ceremony -​ W.H.O: -​ More than 8 million people die from tobacco use each year which includes nicotine: -​ Direct tobacco use: more than 7 million deaths are due to direct tobacco use -​ Second hand smoke: around 1.3 million deaths are due to non-smokers being exposed to secondhand smoke -​ Tobacco use is a leading risk factor for many health conditions, including cardiovascular and respiratory diseases and over 20 types of cancer -​ Tobacco use also contributes to poverty by diverting household spending from basic needs -​ In canada more than 45,000 people die from smoking tobacco each year -​ In 2020 approx 46,000 people died from tobacco use 31 Oct 2024 Week 9.2: Cannabis -​ Cannabinoids: -​ Endocannabinoids (within) -​ Naturally occurring in animals -​ Anandamide -​ Discovered in 1992 -​ Resembles and operates like THC -​ Sanskrit for the “blessed molecule” -​ 2-AG -​ Phytocannabinoids (from plants) -​ From plants  -​ THC, CBD (anxiolytic), CBG, and many others -​ Cannabis plant is indigenous to asia -​ Female cannabis plant is typically the one that is used -​ Synthetic -​ Aren't as popular in Canada because weed is legal -​ Very dangerous, sold in head shops -​ K9, Spice -​ History - China: -​ Shen-Nung c.2700 B.C. -​ He prescribed cannabis also was in the tea lecture -​ “Protracted taking may make one fat, strong, and never senile” -​ History – India: -​ Ganja, Bhang (cannabis milkshake), used on Holi -​ The Vedas call cannabis a source of happiness, joy-giver, liberator that was compassionately given to humans to help s attain delight and lose fear -​ History – Europe: -​ William Brooke O’Shaughnessy -​ Introduced medical use of cannabis to Europe -​ He reported that cannabis was an effective… -​ Anticonvulsant, antispasmodic and an appetite stimulant -​ Treatment for: -​ nausea , neuralgia, dysmenorrhea, asthma Gonorrhoea,