PYB260 Week 8 Lecture: Cannabis (2024) PDF

PYB260 PSYCHOPHARMACOLOGY OF ADDICTIVE BEHAVIOUR Week 8: Action & Effects of Cannabis/Cannabinoids Melanie White, QUT  Lecture Outline What is cannabis? History Administration, distribution & excretion Effects of cannabis – physiological & pe...

PYB260 PSYCHOPHARMACOLOGY OF ADDICTIVE BEHAVIOUR Week 8: Action & Effects of Cannabis/Cannabinoids Melanie White, QUT  Lecture Outline What is cannabis? History Administration, distribution & excretion Effects of cannabis – physiological & performance Conditioning, tolerance & withdrawal Harmful effects  Reflection Questions (egs, not exhaustive) Describe the absorption, distribution & excretion profile of THC from oral vs inhalation routes of admin. What are the impacts for intended medicinal vs. recreational use desired properties? Explain the action of cannabinoids at the different CB receptors, the locations of these receptors & how these give rise to different effects Describe 3 medically beneficial potential effects of cannabinoids & name a drug licensed in Australia for some of these effects Your friend is a heavy and frequent cannabis user and is known for being quite forgetful and easily distracted. Based on the results of animal studies, what might be a mechanism linking their cannabis use to these problems? Based on human fMRI evidence, what pathway may underlie their craving and compulsion to keep using?  What is cannabis? & The history of cannabis use  What is cannabis? Cannabis sativa Plants vary in size; male & female plants Female plant must be fertilized by pollen from male plant to generate seeds Female plant produces sticky resin at top to attract pollen & protect seeds  What is cannabis? Active ingredient: Over 60 cannabinoids (all found only in cannabis) Amount of active ingredient Delta-9-tetrahydrocannabinol (delta-9-THC), depends on: Preparation Route of administration Inactive ingredients altering potency or metabolism All parts of plant contain THC Burning cannabis, GI digestion & metabolism can create new cannabinoids  What is cannabis: Preparations Forms of cannabis: Marijuana: dried leaves & flowers; usually smoked (joint or bong) Hashish: dried resin from female plant; usually smoked, eaten (foods) Hash oil*: hashish boiled in alcohol, then residue is filtered & alcohol evaporated; can be smoked Concentrates: extracts (dabs, wax, shatter), use butane hash oil as solvent & vaporised in small quantities (high THC) Edibles: foods containing cannabis ‘Medicinal cannabis’ – TGA approved, capsules/oral solutions THC content of plants: changes over time 1960’s – 1.5% 1990s – 3.5 - 4.5% 2008 – 10% Can be as high as 30% but typically contain 3-15% THC (see NSW study stats next slides; Swift et al., 2013). Industrial hemp contains < 0.5 - 1% THC by Aus. & NZ laws & regulations.  Table 1. Profile of cannabinoid content (w/w%) in n = 206 samples of cannabis seized during the NSW cannabis cautioning program (October 2010–October 2011). Swift W, Wong A, Li KM, Arnold JC, et al. (2013) Analysis of Cannabis Seizures in NSW, Australia: Cannabis Potency and Cannabinoid Profile. PLoS ONE 8(7): e70052. doi:10.1371/journal.pone.0070052 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070052 Table 2. Profile of cannabinoid content (w/w%) in Indoor and Outdoor Grown “Known Provenance” cannabis samples seized during the NSW cannabis eradication program, February-May 2012. “Despite a wide range, 74% of street-level Cannabis Cautioning samples and 77% of Known Provenance samples contained at least 10% THCtot. Further, 43% of Cannabis Cautioning and 54% of Known Provenance samples contained at least 15% THCtot, the level recommended by the Garretsen Commission as warranting classification of cannabis as a “hard” drug in the Netherlands.” Swift W, Wong A, Li KM, Arnold JC, et al. (2013) Analysis of Cannabis Seizures in NSW, Australia: Cannabis Potency and Cannabinoid Profile. PLoS ONE 8(7): e70052. doi:10.1371/journal.pone.0070052 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070052  Uses of cannabis Historically, hemp has been used for it’s: Fibre (e.g., clothes/textiles, paper, rope) Oil (lamp oil & food) & as an ingredient in the manufacture of soap, paint & varnish (seeds) Medicinal purposes Psychoactive properties It continues to be used for at least some of these purposes  Pharmaceutical cannabinoids Several pharmaceutical preps have been developed for medicinal purposes; some are licensed. Marinol (dronabinol –THC extracted from cannabis) & Nabilone (Cesamet – entirely synthetic THC): to alleviate nausea & vomiting in people w. cancer undergoing chemo & radiation therapy; anorexia & weight loss assoc. AIDS Sativex (THC + CBD (+other cannabinoids + non-cannabinoids) extracted from cannabis): neuropathic pain assoc. multiple sclerosis Epidyolex (CBD extracted from cannabis): approved in Aus (TGA, Sept 2020) for use for seizures associated with rare epileptic disorders (Lennox- Gastaut syndrome or Dravet syndrome); recently added to PBS  History of cannabis Cannabis has been used since before recorded history 3000 B.C. – Chinese herbal remedy 2737 B.C. – ‘superior herb’ in China 1400 B.C. – religious & cultural use in India 450 B.C – consuming cannabis & making hemp 100 – medical uses 400 – cultivated in the UK 800 – Mohammed bans alcohol but allows cannabis 1150 – hemp used for Europe’s first paper mill (Hemp used for paper over next 750 years) 1563 – QE1: land owners must grow hemp or be fined 1611 – British grow cannabis in Virginia 1621 – Anatomy of Melancholy claims cannabis treats depression 1841 – W.B. O’Shaughnessey introduces cannabis as an analgesic, anticonvulsant & appetite stimulant 1860 – Governmental commission study of cannabis & hashish listing medical uses (see next slide)  History of cannabis Medical uses (1860 commissioned study into…) Rheumatism Palsy Mania Uterine haemorrhage Whooping cough Dysmenorrhea Asthma Hysteria Bronchitis Alcohol withdrawal Spasms Loss of appetite Epilepsy Convulsions  History of cannabis 1868 –possession illegal in Egypt 1870 – South Africa prohibits Indians from smoking 1877 – Sultan of Turkey makes cannabis illegal 1911 – South Africa bans cannabis 1915 onwards – states outlaw cannabis 1912 - 1st Opium Conference: suggestion - cannabis to be banned internationally 1924 – 2nd International Opiates conference: Egypt declares harmful effects of cannabis – cannabis declared a narcotic 1928 – UK Dangerous Drugs Act – cannabis illegal 1943 – US Military Surgeon magazine claims cannabis no more harmful than tobacco 1944 – La Guardia report - pro 1968 – Wootton report - pro 1970 – LeDain report – pro 1970 – Controlled Substances Act (US) – cannabis no potential medical use & high potential for abuse 1973 – US Shafer Commission – pro 1976 – Ford bans medical research 1977 – Carter for legalisation 1996 – California & Arizona pass propositions to use cannabis in certain illnesses  History: Some important Australian dates/facts Cannabis little used pre-1960s (prior use primarily medicinal). 1987 – S.A. decriminalises minor cannabis offences 1992 – Australia licenses industrial hemp farm 1993 – ACT partial decriminalisation ‘small amounts’ possession 1996 – NT decriminalises cannabis possession (small amounts) Most states now have ‘cautioning’/drug diversion’ legal options available 2020 – ACT allows adults to cultivate ingestion Peak [C]: 1-4 hrs>ingestion; psychoactive effects THC may last 4-12 hrs, appetite >24 hrs But Absorption is slow & affected by considerable 1st pass metabolism by liver ~5-20% THC & 6-19% CBD molecules reach sites of action (Borgelt et al., 2014); oral medicinal pill 10-20% reaches systemic circulation (US NIH, 2015) Oral vs. inhalation: 1/3 potency; more likely assoc. vomiting & nausea  Ionization of drug molecules pKA Theoretical curve for weak acid with pKA=10.6 (adapted from McKim & Hancock, 2013, Fig. 1-7, p.15)  Administration & absorption & distribution Inhalation Readily and rapidly absorbed 10-25% of cannabinoids reach general blood circulation from lungs (losses through burning, sidestream smoke, metabolism in lungs) Peak blood levels ingestion Excreted in faeces (65%) & urine (20%) Effects of frequent use on metabolism: unclear CBD: ½ life: 9-32 hrs Effects of cannabis  Neuropharmacology Receptor sites 2 known types of cannabinoid receptors (potentially up to 5) Work on second messengers & neuromodulators CB1 Located in CNS: hippocampus, cerebellum, basal ganglia, hypothalamus, & nucleus accumbens, cortex, brain stem, spinal cord Uneven distribution of receptors in the CNS Most in higher centres  affect memory, emotional expression, mental processes; but also affect movement, appetite & analgesia CB2 Mostly outside the CNS in spleen & immune system; could account for effects on immune functioning (immunosuppressive = anti- inflammatory) In CNS: glial cells, stem-like cells, & other brain areas  Neuropharmacology Endogenous Ligands (endocannabinoids) Anandamide Fat soluble, but simpler molecular structure Exact function unknown Discovery has lead to abundance of research The function of endocannaboids: “Relax, eat, sleep, forget & protect”  Neuropharmacology: Neuromodulating effects of THC & endocannabinoids Alters functioning of: GABA, NE, DA, 5-HT, ACh, Histamines, glutamate, & Opioid peptides. Endocannabinoids synthesized “on-demand” in dendrites & cell body then released, cross synapse & bind to presynaptic CB1 Rs Retrograde action – allow the postsynaptic neuron to shut down presynaptic neuron Depolarization-induced suppression of inhibition (DSI) Depolarization-induced suppression of excitation (DSE) Examples of 3 specific types of neuromodulation:  synthesis of: Alter receptors for: Potentiate action of: - NE - NE - NE - DA - ACh - ACh - 5-HT - DA - DA - GABA  Neuropharmacology: Reinforcement of cannabinoids Reinforcing effect of cannabinoids: CB1 receptors located with DA receptors in mesolimbic DA pathway regions (midbrain, pfc, basal ganglia) CB1 receptor stimulation  inhibitory actions of GABA neurons projecting onto DA neurons in the Nacc  DA neuron firing here &  striatal DA release + DA neurons in VTA synthesise & release endocannabinoid when stimulated  DA neuron firing  Neuropharmacology: Reinforcement of cannabinoids Reinforcement via opioid receptors: CB1 also overlap & interact with μ opioid receptors in Nacc Conditioned place preference to THC abolished by μ opioid receptor knockout Opioid antagonist naloxone blocks both THC self-administration & THC- induced DA release in Nacc Naltrexone  cannabis use & positive subjective effects in daily marijuana smokers CB1 receptors seem to be important for reinforcing effects & devt of phys. dependence of some opioids (morphine & heroin) *THC & AEA partial agonists of CB1 (& CB2 & other sites), cannabidiol does not act via these sites  Effects of cannabis: on the body Low-moderate dose: Dilation of small blood vessels in eyes Dry mouth, thirst Hunger (max 3hrs>smoking; tolerance after few weeks)  BP @ low doses/repeated use ( BP @ high doses) Body temp changes  HR  cortisol Headache, dizziness, nausea/vomiting  Effects of cannabis Sleep  drowsiness,  time to fall asleep,  sleeping time, REM High doses cause insomnia; chronic use: LT  slow-wave sleep Habitual use, tolerance to sleep-latency but not to REM Withdrawal effects:  time to fall asleep,  awakenings, total sleep time & quality, vivid dreams, slow-wave sleep, REM rebound Perception Blurred vision Usually no change in sensory thresholds (vs. subjective report)  pain sensitivity slowing in time rate (time distortion effects)  Effects of cannabis On memory Disrupts ability to recall verbal material STM (dose-dependent impairments) Temporal disintegration Smaller right hippocampal volume in high adolescent users (5.8 joints/day) (Ashtari et al., 2011) On attention  performance on vigilance tasks/ sustained attention  concentration On creativity No evidence  Effects of cannabis On mood – at typical doses: Gaiety – dreaminess Anxiety/panic Variability in subjective mood & arousal ratings Depends on environment & mood of others On performance Variable Depends on experience, instructions, motivation, setting, dose, performance task In general, choice RT & complex tasks most impaired; chronic users less impaired while intoxicated than occasional users (tolerance to some effects)  Effects of cannabis On driving  performance for most people; potentiated by alcohol  ability to attend to peripheral stimuli Currently illegal to drive with THC in Aus (except Tas.) but recent push for exemptions for medicinal use if not impaired (e.g., NSW, Vic, WA govts) “Medically beneficial” effects  nausea/vomiting – cancer treatments (not as first line treatment) nabilone (Cesamet) & dronabinol (Marinol) -synthetic cannabinoids Anticonvulsant (epilepsy, CBD, e.g., Epidyolex) & spasticity (MS, e.g., Sativex/nabiximols) Modulating pain  BP in eye – glaucoma  Cannabis & psychosis Acute effects (typically high doses): ‘drug-induced psychosis’ - Distorted perception, anxiety, panic, paranoia, psychotic-like experience - CBD may counteract such THC effects (Morrison et al., 2009) Longer-term effects: risk of psychosis & schizophrenia (trigger 1st episode of psychotic illness; make pre-existing psychotic illness worse) Methodological flaws in this research: - Correlational (cause or effect or mediated by 3rd variable?) - Includes large dose/chronic users - Small sample sizes Studies addressing such flaws, e.g., large, longitudinal study of military conscripts adolescence->next 35 yrs (Manrique-Garcia, 2011): frequent users 3.7 x more likely to develop schizophrenia, 2.2 x brief psychosis & 2.0 x more likely other psychoses Cannabis use seems to be a risk factor for psychosis. May be a trigger in individuals with a predisposition to psychosis  THC: a lethal dose? Phylogenetically higher animals are less susceptible to acute toxicity of THC LD50 of THC administered intravenously is 40mg/kg in rats vs. 130mg/kg in dogs & monkeys (Rosencrantz, 1983; min. lethal dose in dogs is 3mg/kg – Fitzgerald et al., 2013). No experimental evidence to determine a lethal dose in humans no reported deaths attributable to cannabis OD in the world medical literature* [there are from synthetic cannabinoid use] Extrapolation from animal evidence (i.e., monkey) ~ LD50 dose of THC in a 65kg adult would be 8.45kg. *There are studies reporting deaths “attributable to cannabis” – e.g., Imtiaz et al., 2016, doi: 10.1111/add.13237. Conditioning, discrimination, tolerance & withdrawal effects of cannabis  Conditioning & discrimination Unconditioned behaviour (in animals) Mice: ‘Cannabinoid tetrad’ dose-dependent effects (SMA, muscle rigidity, pain sensitivity, & hypothermia). Biphasic effect on SMA: activity followed by  SMA High doses – ataxia Feeding dependent on dose, route of admin, & timepoint: inhalation of vaporized THC  food intake in rats in 1 st hour High doses -  appetite & subsequent weight loss  sweet preference  aggression (taming effect)  response to painful stimuli (THC as potent as morphine)  Conditioning & discrimination Conditioned behaviour (in animals) THC interferes with STM tasks (correlates with  neuronal firing in hippocampus in rats) Research mixed on effects on LTM Some evidence that chronic use during adolescence leads to adult deficits in spatial memory (monkeys) & STM (rats)  avoidance responding but not escape responding Does not affect punished responding  Conditioning & discrimination Discrimination (animals) Reliable discrimination of THC from placebo Delta-9-THC generalizes to: Delta-8-THC Nabilone 11-hydroxy metabolite CBN Partial generalisation to sedatives Does not generalize to CBD, anandamide (unless at high doses of anandamide), or drugs from other classes Discrimination (humans) Humans can discriminate marijuana cigarettes which don’t contain THC 0.09 % Dissociation in animals & humans (state dependent learning)  Self-administration Animals self-administer, but not reliably intravenously. Rats will lever-press for THC injections to VTA or NAcc In lab studies humans have fairly stable intake Titration Some studies show titration of dose (e.g., alter puffing depending on potency of joint) Others show inability to account for different potencies May be more reinforcing if higher THC content (e.g., 1.95% vs. 0.63%)  Tolerance & withdrawal Tolerance – in animals Develops rapidly (5-6 days) to many effects Tolerance develops to:  SMA  SMA (slower to develop) Tolerance does not develop to: Anorexic effects Discrimination Tolerance lasts for > 1 month & there is cross-tolerance btwn delta-9 THC & its 11-hydroxy metabolite Assoc. with  CB1 receptors in some brain regions & down- regulation/desensitization of receptors  Tolerance & withdrawal Tolerance in humans Tolerance seen more consistently with high doses and continuous/very frequent use Tolerance develops to acute neurocognitive impairment & most subjective psychological effects, possibly involves downregulation of CB1 receptors (e.g., see Colizi et al., 2018 systematic review; Ramaekers et al., 2020 narrative review; Mason et al., 2019 fMRI placebo-controlled experiment of 12 casual cannabis users vs 12 chronic cannabis users) No tolerance to increased food consumption  Tolerance & withdrawal Withdrawal (in animals) In continuous admin. of high doses Typically mild symptoms (e.g.,  SMA in rats) Withdrawal symptoms may be masked by long ½ life Injection that blocks CB receptors →withdrawal: stress hormones Withdrawal (in humans) Onset 1-3 days post abstinence, peaks 2-6 days, lasts for 2 wks; typically mild: Irritability, restlessness, insomnia, anxiety, depressed mood Hot flashes, sweating, runny nose, diarrhea, hiccups,  appetite Cravings for cannabis (comparable to tobacco withdrawal) Oral THC capsules can alleviate withdrawal symptoms  Cannabis Use Disorder Systematic review & meta-analysis of 21 studies of the risk of CUD from use (Leung et al., 2020): Cannabis use ~ 1 in 5 risk of developing a CUD; 13% had cannabis dependence Risks of developing cannabis dependence  to 33% if cannabis is initiated early & used frequently (weekly/daily) https://doi.org/10.1016/j.addbeh.2020.106479 Harmful effects of cannabis: ongoing controversies  Harmful effects On reproduction Males:  testosterone, sex drive (dose-dependent),  sperm motility Interferes with fertility in females (anandamide & fertility)  risk miscarriage, preterm birth, & fetal growth restriction; mild cognitive impairments, attentional & mood disorders in these children Abnormal sleep patterns of newborns Chromosomal damage → All research questionable & mixed results found On immune system Complex but includes  immune functioning  Harmful effects On respiration Acute effect: bronchodilation – helpful in asthma Repeated cannabis smoking  inflammation of large airways, increase in airway resistance, & lung damage similar to cigarette smoking  activity of macrophages  risk of respiratory disease associated with smoking, including cancer On cancer more carcinogens than tobacco Inhale more tar than tobacco May accelerate carcinogenic effects of tobacco smoke Antioxidant effects of THC & CBD?  Harmful effects Violence No empirical evidence; though widely held belief Usually show  hostility Mental disturbance Paranoia & anxiety (large doses) Acute psychotic episode Can precipitate psychosis in people with psychotic tendencies  Harmful effects Brain damage (LT use) loss of mental functioning (mild), dose/recency effects Animal research has found: Altered brain structure (hippocampus)  neuronal plasticity & learning Amotivational syndrome Evidence from clinical observations Causal relationship? Confounds in studies…more recent studies better designed & show acute effects on motivation/choice to engage in less effortful/lower reward tasks over more effortful/higher reward tasks Altered reward response in nucleus accumbens (fMRI studies)  Nacc response to monetary reward anticipation (Martz et al., August 2016) ↑ mesolimbic response to cannabis cues vs. fruit rewards (Filbey et al., May 2016)  Harmful effects Cannabis as a gateway drug High correlation but no causal evidence Social not physical Or personality variables (common factor model)  Conclusion At the end of this lecture you should: Know what cannabis is & common types of cannabinoids Have an understanding of the history of cannabis use Be familiar with administration, distribution & excretion of cannabis Understand the effects of cannabis (physiological & behavioural & variables that mediate these effects) Know about cannabis conditioning, tolerance & withdrawal Understand the harmful effects of cannabis  Reflection Questions (egs, not exhaustive) Describe the absorption, distribution & excretion profile of THC from oral vs inhalation routes of admin. Impacts for intended medicinal vs. recreational use desired properties? Explain the action of cannabinoids at the different CB receptors, the locations of these receptors & how these give rise to different effects Describe 3 medically beneficial potential effects of cannabinoids & name a drug licensed in Australia for some of these effects Your friend is a heavy & frequent cannabis user & is known for being quite forgetful & easily distracted. Based on the results of animal studies, what might be a mechanism linking their cannabis use to these problems? Based on human fMRI evidence, what pathway may underlie their craving and compulsion to keep using?  Reminders Tutorials today: Lab Report Q&As No classes next week – lab reports due Week 10 (after mid-sem break): Lecture: Alcohol Tutorials: Exam prep #1 – bring your notes & textbook All the best in finalising your lab reports & we hope you have a relaxing mid- semester break!