Marijuana.pdf

14 Marijuana and Cannabinoids https://www.motherjones.com/media/2019/03/emily-post-great-great-granddaughter-higher-etiquette-cannabis/ “But I would not feel so all alone, Everybody must get stoned” Rainy Day Woman # 12 & 35 Bob Dylan, Nobel Prize in Literature, 2016 Legalize it https://disa....

14 Marijuana and Cannabinoids https://www.motherjones.com/media/2019/03/emily-post-great-great-granddaughter-higher-etiquette-cannabis/ “But I would not feel so all alone, Everybody must get stoned” Rainy Day Woman # 12 & 35 Bob Dylan, Nobel Prize in Literature, 2016 Legalize it https://disa.com/map-of-marijuana-legality-by-state https://www.nytimes.com/2022/10/06/us/politics/biden-marijuana-pardon.html Medical Marijuana howmedicalmarijuanalawshave changedopioid prescription medical marinvananatural analgesic 86 Lifription Marijuana and the Cannabinoids • Background • Basic Pharmacology • Mechanisms of Action • Acute Behavioral and Physiological Effects • Cannabis Abuse and Chronic Exposure Background Background and History of Marijuana • produced from flowering hemp (Cannabis sativa) • 5000 years ago>>>psychoactive properties recognized in China>>> extracts used for relief of cramps and pain • Brought to the West by Napolean’s troops who returned with Egyptian hashish: “For Egyptians the hemp plant is par excellence, not for the uses they make of it in Europe or many other countries, but for its particular effects. The hemp cultivated in Egypt is indeed intoxicating and narcotic” Piomelli, 2003, p.873 ineuropeused tomakerope fiber • major source of fiber in many cultures for rope, cloth, and paper Background and History of Marijuana • 1930s: US Bureau of Narcotics launched major PR campaign to portray marijuana as a social menace that could destroy the youth of America • Reefer Madness “By the tons it is coming into this country — the deadly, dreadful poison that racks and tears not only the body, but the very heart and soul of every human being who once becomes a slave to it in any of its cruel and devastating forms. ... Marihuana is a short cut to the insane asylum. Smoke marihuana cigarettes for a month and what was once your brain will be nothing but a storehouse of horrid specters. Hasheesh makes a murderer who kills for the love of killing out of the mildest mannered man who ever laughed at the idea that any habit could ever get him…” • Marijuana Tax Act of 1937: discouraged all uses § Made nonmedical use illegal Harry J. Anslinger Background and History of Marijuana A Schedule 1 Drug (DEA): Schedule I Drugs: • drugs, substances, or chemicals with no currently accepted medical use and a high potential for abuse • Schedule I drugs are the most dangerous drugs of all the drug schedules with potentially severe psychological or physical dependence • heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), CBD, 3,4methylenedioxymethamphetamine(MDMA), methaqualone, and peyote http://www.dea.gov/druginfo/ds.shtml Basic Pharmacology Basic Pharmacology • C. Sativa contains >100 unique cannabinoids § Δ9-tetrahydrocannabinol (THC) • Main psychoactive compound • concentrated in the sticky resin>>>secreted by flowering tops of female plants marijuana hathas • THC content (and potency) varies widely THC Average Δ9-tetrahydrocannabinol (Δ9-THC) concentration of DEA specimens by year, 1995 – 2014. Biol Psychiatry. 2016;79(7):613-619. doi:10.1016/j.biopsych.2016.01.004 Basic Pharmacology Raphael Mechoulam ”The father of cannabis research" THC Basic Pharmacology THC (1964) THC •vaporizes and enters lungs in small particles •Effective dose and latency to onset: influenced by the amount and potency of the plant used and patterns of smoking (e.g., hold duration, puff volume, puff frequency) •Metabolized by CYP enzymes in liver: CYP2C9, CYP2C19, CYP3A4 •Metabolites: (>80): •11-hydroxy THC and THC-COOH Tienanmen •present for more than 2 ftp.iiiijijii weeks in urine after a single use § Basis for urine drug screens •11-hydroxy THC>>>psychoactive Basic Pharmacology https://www.yahoo.com/sports/us-long-jumper-tara-davis-woodhall-stripped-of-national-title-after-positive-cannabis-test-234306817.html Basic Pharmacology https://www.nytimes.com/2021/07/01/sports/olympics/shacarri-richardson-suspended-marijuana.html?action=click&module=Top%20Stories&pgtype=Homepage Basic Pharmacology THC •easily absorbed by the lungs>>> blood plasma levels rise quickly •Blood THC levels decline rapidly after smoking>>>Biological half-life is ~20-30 hours •complete elimination from the body is much slower because of persistence in fat tissues (lipid depots) Cigarette w/ 9 mg THC at each arrow Basic Pharmacology Why do edibles (e.g., PO THC) hit you so hard? ie moresystemic • PO THC gets metabolized by the liver>>>delta-9 THC becomes 11-OHTHC § traverses the blood-brain barrier more rapidly and is more potent • A much higher concentration of 11-OH THC is produced PO than inhalation highlysolublebypasses BBBmoreeasilyprocuringmorepotent errecting § ~50% of PO THC becomes 11OH-THC • PO THC takes 30 to 90 minutes for the initial psychoactive effect • the resulting “high” is longer-lasting, with a peak at 2 to 4 hours after ingestion https://www.nytimes.com/2014/06/04/opinion/dowd-dont-harsh-our-mellow-dude.html p THC has a biological half-life of approximately 20-30 hours. What is the main factor contributing to this long halflife? lipidsoluble readilybindstoapical A) THC readily persists in lipid depots in the body B) THC can be ingested orally or via inhalation C) THC content within individual marijuana plants is highly variable D) THC is only metabolized by the liver Mechanisms of Action: Cannabinoid Receptors Mechanisms of Action • First cannabinoid receptor in CNS identified in 1988 § CB1 receptor—widely expressed in body § Not related to any know receptor for NTs or peptides in the brain byAA GPCR widely moggan Gpcrreceptorexpressedin tootherreceptors brain sequence § brain has more CB1 receptors than any other GPCR § CB2 found the immune system and other tissues (bone, adipose cells, GI tract) aimsbutperiphery Mechanisms of Action • CB receptors: metabotropic § Signal via Gi: intracellular gnating § inhibit AC inhibitgypstream § inhibit voltage-gated Ca2+ initial giiiaent channels § open K+ channels efflux nyperpol fi potassium try • Very few CB-1 receptors found in brainstem respiratory centers opioidsisopposite rainorreceptorshereprevents overaoreseam • Majority located on axon terminals (on pre-synaptic cell) § inhibit release of neurotransmitters § THC: a partial agonist at CB1 and CB2 receptors thereare syntheticfullagonist that produce psychosis § Rimonabant: a selective CB1 antagonist: a failed obesity drug in it Mechanisms of Action • CB1 receptor activation>> behavioral tetrad: 1. Reduced locomotor activity 2. Hypothermia i body temp drops 3. Catalepsy lack of spontaneous movement 4. hypoalgesiareduced sensitivity to pain • CB1 receptor activation in hippocampus >>>spatial learning deficits in animals § effects blocked by rimonabant Radialarmmaze tests spatial errors memory looking by reflectis mediatedby lb receptor it we agonite is receptorhippocampustherearedeficits in learning memory non f affinity.it i f I In nonino • antagoni agonist aia IP injection of CP-55940 with rimonabant injection into hippocampus Bihari Mechanisms of Action: Neurobiological Basis for the Munchies riffraff L • Endocannabinoids (and THC): penology enhance incentive motivational munchies properties of food causes • CB1 receptor antagonists reduce food consumption in animals and humans • Rimonabant: approved as an antiobesity medication in the EU from 2006-2008 § Removed from market after adverse psychiatric side-effects alsoantagonizesother CBerects opioid 8 98 shamingcenter depressing inbitingthem preventing individual from breathing In contrast to opioids, there has never been any documented case of an overdose death from marijuana. What fact about cannabinoid receptors likely contributes to this? A) There are very few (if any) CB1 receptors located in the brainstem B) CB1 receptors are located pre-synaptically, not postsynaptically C) Marijuana is only a partial agonist of the CB1 receptor, whereas opioids are full agonists of the opioid receptor D) CB1 receptors are GPCRs that signal through Gi E) CB1 receptor activation causes hypothermia rather than hyperthermia Mechanisms of Action: Endocannabinoids systemboundwithinbody Mechanisms of Action • Why do human brains have receptors for a compound made by plants? • Must be an endogenous neurotransmitter-like substance that acts on the receptors § endocannabinoids Mechanisms of Action I • Two endocannabinoids : 1. arachidonoyl ethanolamide (AEA or anandamide) iii ii partialagonist is 2. 2-arachidonoylglycerol (2AG) majorone on agonist IB an receptor • found in much higher quantities in brain • Main endocannabinoid for CB1 and CB2 receptors § Both bind and activate CB1 receptors • Anandamide: partial agonist • 2-AG: full agonist ff • retrograde messengers: postsynaptic to presynaptic t Mechanisms of Action • Endocannabinoids § Retrograde messengers § Bind selectively to CB1 receptors on presynaptic terminal (majority) calciumsensitive enzymeinvolvedin • Not packaged into vesicles u'm'abinoids hi that her § Manufactured on demand § Synthesized from membrane inositol phospholipids that contain arachidonic acid endocannabinoid embrane • Small lipid molecules tip • membrane permeable § Rise in intracellular Ca2+ >>>Ca2+ sensitiveenzymes produce them: 1. Local depolarizing event causes VGCC’s to open and Ca2+ to enter 2. rise in intracellular Ca2+ stores (via PLC v9 activation) 3. Ca2+ influx via NMDA receptors Mechanisms of Action not tested oh it Novel signaling mechanisms: • anandamide remains within a spine to activate either postsynaptic CB1 receptors or TRPV1 cation channels • endocannabinoids activate CB1 receptors on astrocytes • provoke glutamate release from the cells Mechanisms of Action A cannabinoid membrane transporter? don'tknownow tanenpaun into Metabolic enzymes: • Anandamide: fatty acid amide hydrolase (FAAH) in postsynaptic neuron § 2-AG: monoacylglycerol lipase (MAGL) in presynaptic neuron • MAGL KO mice: significantly increased 2-AG concentrations § develop desensitization of CB1 receptors in CNS due to high 2 A6 http://www.neurology.org/content/69/3/306/F1.expansion.html Mechanisms of Action Depolarization-Induced Suppression of Inhibition (DISI) Hippocampal pyramidal cells: •membrane depolarization opens voltage-activated Ca2+ channels CA1 of hippocampus >>>elevation of intracellular Ca2+ concentrations>>>2-AG production •2-AG diffuses to terminals of GABAergic interneurons that normally suppress firing of pyramidal cell •leads to increased firing of the pyramidal cell III supress GABAinhibition Mechanisms of Action Depolarization-Induced Suppression of Excitation (DISE) In hippocampus, glutamate binds to post-synaptic mGlur5 receptors: • Activates PLC>>>2-AG release • 2-AG diffuses to nerve terminal and and activates CB1 receptors to reduce glutamate release • protective mechanism suprelsexcitation reducefiring https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042796/ Mechanisms of Action if •Endocannabinoids: modulate pain perception and inflammation § WT mice given rimonabant exhibit hyperalgesia (increased pain sensitivity) • CB1 and CB2 KO mice also exhibit hyperalgesia I antagoniedmore pain § believedtobe body's naturalanagini THC given to WT mice leads to hypoalgesia (reduced sensitivity to pain) • WT mice given CB1 agonists do too • Cannabinoids are equipotent with morphine • Robust anti-inflammatory activity of topical THC • reduced recruitment of mast cells, decrease histamine, decreases in myeloid immune cell infiltration Mechanisms of Action Montgomery https://www.nytimes.com/2019/03/28/health/woman-pain-anxiety.html • • minor very a loss of function of FAAH! No pain Mechanisms of Action “Last dance with Mary Jane One more time to kill the pain” Mary Jane's Last Dance Tom Petty and the Heartbreakers Mechanisms of Action Endocannabinoids and fear learning: • Endocannabinoids facilitate extinction of learned fear responses § Rimonabant inhibits extinction • CB1-receptor enhancing drugs for for PTSD? Day 1: Single conditioning session Day 2: Rx then returned to apparatus with tone continuously presented in absence of shock Mechanisms of Action Endocannabinoids and fear learning: • In humans, a SNP in FAAH gene results in increased endogenous anandamide levels • People with one copy of hypofunctioning allele habituated much quicker to images of threatening faces § Increased anandamide levels enhance the ability to “turn off” responses to threatening stimuli Endocannabinoids are different from classic neurotransmitters because they are not packaged into vesicles prior to release. What prevents packaging of these molecules into vesicles? A) They are synthesized from membrane lipids B) They are retrograde messengers C) They are released following an intracellular rise in calcium D) Endocannabinoid receptors are GPCRs E) They are larger than classic neurotransmitters F) They are smaller than classic neurotransmitters Mechanisms of Action: CBD Mechanisms of Action CBD (Cannabidiol) • Isolated by Mechoulam in 1963 • one of the 100+ cannabinoid chemicals in the marijuana plant • Lacks psychoactive effects of THC: No longer schedule 1 • Very low affinity for CB-1 or CB-2 receptors • Effective as an anticonvulsant, antianxiety, analgesic, antitumor, antipsychotic • More cannabinoid receptors? CBD https://www.nytimes.com/interactive/2019/05/14/magazine/cbd-cannabis-cure.html?referringSource=articleShare CBD Epidiolex • The panel recommended approval of the drug to treat two rare forms of epilepsy — Lennox-Gastaut syndrome (appears between 3 and 5) and Dravet syndrome (<3). • ~30,000 children and adults with Lennox-Gastaut syndrome, less with Dravet syndrome • patients continuing to have multiple seizures/day despite medication • Leads to at high risk for intellectual and developmental disabilities, as well as death. CBD https://www.usatoday.com/story/news/2 018/12/21/hemp-cbd-farm-bill-signingtrump-delawareagriculture/2387656002/ https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm628988.htm CBD CBD Histiocytoma Before 1.5 weeks 2.5 weeks 3.5 weeks Topical treatment with CBD oil 1x/day CBD https://www.nytimes.com/2023/01/26/health/fda-cbd-oversight.html?smid=nytcore-ios-share&referringSource=articleShare Why does CBD not have the same psychoactive effects as THC? A) CBD has a low affinity for both CB1 and CB2 receptors B) CBD has a high affinity for CB1 receptors but low affinity for CB2 receptors C) CBD has a high affinity for CB2 receptors but low affinity for CB1 receptors D) CBD is an antagonist of the CB1 and CB2 receptors E) CBD is not metabolized by CYP enzymes Acute Behavioral and Physiological Effects Acute Behavioral and Physiological Effects of Cannabinoids • Subjective and behavioral effects of marijuana use can be separated into four stages: 1. the “buzz,” 2. the “high,” 3. being “stoned” 4. the “come-down” • “high” is associated with feelings of euphoria and exhilaration, and a sense of disinhibition • Relaxation is the most commonly reported effect of being “stoned” Acute Behavioral and Physiological Effects of Cannabinoids • Physiological responses: § increased blood flow to the skin and flushing, increased heart rate, and increased hunger § THC acts on CB1 receptors in blood vessels • Relaxation >>> vasodilation • effects are reduced by pretreatment with rimonabant Acute Behavioral and Physiological Effects of Cannabinoids Reinforcing properties of cannabinoids: • Lever pressing by squirrel monkeys for THC stops when saline is substituted • Lever pressing for THC is completely blocked by pretreatment with rimonabant § reinforcing effect is dependent on CB1 receptor activation • • • Physiologically relevant doses (e.g., a single puff on a joint) 1 hr sessions IV admin Acute Behavioral and Physiological Effects of Cannabinoids Mechanisms for reinforcement: •Activation of the mesolimbic dopamine (DA) system § stimulate firing of VTA neurons in VTA and enhance DA release in NAcc • opioid agonists enhance cannabinoid selfadministration • opioid antagonists have the opposite effect http://openi.nlm.nih.gov/imgs/512/281/2958859/2958859_1755-7682-3-24-1.png Cannabis Abuse and the Effects of Chronic Cannabis Exposure Cannabis Abuse and the Effects of Chronic Cannabis Exposure Tolerance • Animals exposed to THC or other CB1 agonists develop tolerance to the behavioral and physiological effects § Involves a combination of desensitization and down-regulation of CB1 receptors • Are these doses relevant to human consumption? Cannabis Abuse and the Effects of Chronic Cannabis Exposure Animal studies of chronic THC administration: § no withdrawal signs: • long elimination half-life of THC § Cannabinoid receptors remain partially activated •Rimonabant § Precipitated withdrawal—rimonabant blocks the receptors and even with THC present • Decreased DA firing in VTA and reduced DA release in NAcc • Increased CRF release in amygdala § animals show abstinence symptoms § used very high doses Cannabis Abuse and the Effects of Chronic Cannabis Exposure • ~40 millions regular users • ~8 million meet criteria for dependence (“Cannabis Use Disorder” • ~6.5 % of users suffered moderate to severe disorder Cannabis Abuse and the Effects of Chronic Cannabis Exposure https://www.ncbi.nlm.nih.gov/books/NBK538131/ Cannabis Abuse and the Effects of Chronic Cannabis Exposure CB1 receptor activation and brain development? • Chronic treatment of adolescent rats with CP-55,940 (CB1 receptor agonist) reduced PFC dendritic length and impaired LTP at hippocampal–PFC synapses Cannabis Abuse and the Effects of Chronic Cannabis Exposure Adverse Health effects: • No reports of death from overdose • Smoking damages lungs—smoke contains tar, carcinogens, carbon monoxide, etc. § Vaping Cannabis Abuse and the Effects of Chronic Cannabis Exposure Cannabis Abuse and the Effects of Chronic Cannabis Exposure • Chronic low dose THC reversed age-related cognitive decline in mice aged 12-18 months • Accompanied by enhanced expression of synaptic proteins and increased spine density in hippocampus • Hippocampal gene expression in 12-month old THC treated mice resembled patterns in 2-month untreated mice Cannabis Abuse and the Effects of Chronic Cannabis Exposure THC and reproductive functions: • Suppresses release of LH (luteinizing hormone) • In men, regular smoking decreases testosterone levels and sperm counts § Animal work: demonstrated pregnancy failure, retarded embryonic development, and fetal death with THC administration • has not yet been reported in controlled human studies Cannabis Abuse and the Effects of Chronic Cannabis Exposure Say What? https://www.ada.org/about/press-releases/half-of-dentists-say-patients-are-high-at-dental-appointments While the long-term health effects of chronic cannabis exposure are still being studied, we did discuss several interesting findings that have been published to date. Which of the following health effects have been linked with long term cannabis use? A) Enhanced long term potentiation in adolescent rats B) An increased risk for gum disease in humans in middle age C) An increase in age-related cognitive decline in mice D) A decrease in sexual frequency in humans Synthetic Cannabinoids and Delta-8-THC Synthetic Cannabinoids • Synthetic designer cannabinoids – “K2” or “Spice.” § First appeared in 2004 § experiences similar to those produced by marijuana—elevated mood, relaxation, and altered perception § Some users report psychotic effects: extreme anxiety, paranoia, and hallucinations § Schedule I in 2011 § K2 od Synthetic Cannabinoids https://www.the-scientist.com/news-opinion/how-k2-and-other-synthetic-cannabinoids-got-their-start-in-the-lab-65145?utm_campaign=TS_DAILY%20NEWSLETTER_2018&utm_source=hs_email&utm_medium=email&utm_content=67872845&_hsenc=p2ANqtz-8pJs2F-Cpz72KDNbsa_cpPAGvkU60w9efZIWxI14Kw73hlz1tDynf43SsiHPUIRFvWCz1dLkXDRRywuB2vyhhWNbmOw&_hsmi=67872845 Delta 8 THC https://www.fda.gov/consumers/consumer-updates/5-things-know-about-delta-8-tetrahydrocannabinol-delta-8-thc