5/14/2020

Caring for the

PRESENTER Janice Newell Bissex, MS, RDN Bonnie Johnson, MS, RDN

1

Disclosures

Bonnie Johnson, MS, RDN:

• Editorial Board and Contributor to CRx Magazine (Great Valley Publishing)

Janice Newell Bissex, MS, RDN:

• Editorial Board and Contributor to CRx Magazine (Great Valley Publishing)

• Owner, Jannabis Wellness and Jannabis Wellness (hemp CBD products)

#TDVirtualSymposium 2

Getting Familiar with the ECS: Learning Objectives At the end of this session, participants will be able to:

1. Identify 2 receptors and 2 ligands of the endocannabinoid system (ECS).

2. Discuss the role of the endocannabinoid system in the etiology of migraine, fibromyalgia, irritable bowel syndrome, and other conditions.

3. Explain the role of and CBD in the regulation of the ECS.

4. Discuss the different methods of cannabis or CBD administration, and why some might be more effective than others based on potential drug interactions, condition, and lifestyle.

#TDVirtualSymposium 3

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EAT SLEEP

RELAX

FORGET

PROTECT

The Endocannabinoid#TDVirtualSymposium System DiMarzo, 1998. 4

Timeline of Discovery

• First plant • Roger Adams at the • Raphael Mechoulam at • First cannabinoid University of Illinois Hebrew University —CB1—is (phytocannabinoid) discovers a second isolates another discovered in the brain isolated: cannabinoid: cannabinoid: of rats and confirmed 1940 1964 1988 • (CBN)1 • (CBD)2 • Δ-9- in humans. tetrahydrocannibinol Researchers show that Century (THC)3 CB1 receptors are the most prevalent th receptor in the brain.4,5 End End 19

1. Pertwee, 2006 2. Adams, et al., 1940 3. Mechoulam, 1973 4. Devane, et al., 1988 5. Matsuda, et al., 1990 #TDVirtualSymposium 5

Timeline of Discovery

• Raphael Mechoulam • A second cannabinoid • A second • The first time the term and a global team of receptor—CB2—is endocannabinoid is “Endocannabinoid researchers discover an found in the heart, discovered: System” appears in endogenous blood vessels, 3,4 peer-reviewed

1992 1993 1995 • 2-AG 2000 cannabinoid: kidneys, bones, literature5 (AEA), intestines, spleen, that interacts with CB1 reproductive organs, receptors similar to and lymph system.2 THC.1

1. Matsuda, et al., 1990 2. Devane, et al., 1992 3. Munro, et al., 1993 4. Stella, et al., 1997 5. Piomelli, et al., 2000 #TDVirtualSymposium 6

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Timeline of Discovery

• Endocannabinoid Deficiency • The National Academies of proposed as underlying Sciences, Engineering, cause of Migraine, Medicine publish book: The 2008 Fibromyalgia, Irritable 2017 Health Bowel Syndrome.1 and : The Current State of Evidence and Recommendations for Research.2

1.Russo, 2008 2.National Academies of Sciences, 2017 Image Credit: VectorStock 1783376 #TDVirtualSymposium 7

The Endocannabinoid System (ECS) • Receptors • CB1 • CB2 • Messengers • Anandamide (AEA) • 2-AG • • FAAH • MAGL

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Endocannabinoid Receptors

• G Protein-Coupled Receptors (GPRC) • The “inbox” for messages sent between cells.

• 1 (CB1) • The most abundant G protein-coupled receptor (GPCR) expressed in the brain. • Also found in the peripheral nervous system, fat cells, liver & musculoskeletal tissues1

• Cannabinoid receptor 2 (CB2) • A G protein-coupled receptor primarily located on immune cells • Also found on the spleen, tonsils, and thymus glands • Are found localized on monocytes, macrophages, B-cells and T- cells2 • CB2 receptors are also found in the peripheral nervous system, GI tract, and central nervous system.3

• GPCR are an important drug target.4 1.Glass, et al., 1997 2.Onaivi, 2011 3.Atwood, et al., 2010 #TDVirtualSymposium 9

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Endocannabinoids1

• Messengers: • The endocannabinoids (also called ECS ligands) are the messengers that connect with receptors and start biochemical cascades to maintain homeostasis.

• Anandamide • also known as N-arachidonylethanolamide • AEA

• 2-AG • also known as sn-2-arachidonoylglycerol

• AEA and 2-AG are released from phospholipids embedded in cell membranes and released on-demand or only when they are needed. • AEA and 2-AG cannot be packaged and stored for later use unlike other biological messengers.

1.DiMarzo, 1998 #TDVirtualSymposium 10

Endocannabinoid Enzymes • Enzymes that breakdown the two main cannabinoids are embedded in the cell membranes • Fatty Acid Amide Hydrolase (FAAH) • Breaks down anandamide (AEA)1 • Monoacylglyceral Lipase (MAGL) • Breaksdown 2-AG2 • Because endocannabinoids function in homeostatic fashion, they are broken down as soon as they deliver their messages to the receptors

1.Bisongo, et al., 2002 2.Dinh, et al., 2002 #TDVirtualSymposium 11

ECS Deficiency Syndrome1 • All humans have a personal “endocannabinoid tone”: • Production of the endocannabinoids AEA and 2AG • Metabolism of endocannabinoids by FAAH and MAGL • The number and sensitivity of cannabinoid receptors CB1 and CB2

• ECS tone can be genetic or affected by external factors

• When ECS tone becomes deficient, it can produce symptoms like: • Hypersensitivity to pain • Associated with symptoms of migraine (photo and phonophobia) • Reduced threshold for pain • Associated with chronic pain in fibromyalgia • Chronic inflammation • Associated with changes in GI tract anatomy and secretions

1. Russo EB. 2016 #TDVirtualSymposium 12

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Three Ways to Regulate the ECS • Increase ECS messenger biosynthesis (↑ AEA and 2-AG) • Short term steroid use may ↑ AEA in the brain.1 • Exercise may ↑ AEA and 2-AG in short term.1 • supplements may ↑ synthesis of AEA.2 • Obesity may ↑ AEA and 2-AG.2

• Decrease ECS metabolic activity (inhibit FAAH and MAGL) • NSAIDS + Acetaminophen may block FAAH which stops the breakdown of AEA which may influence pain perception.3,4

• Increase/decrease number of and/or sensitivity of cannabinoid receptors • Probiotics/prebiotics may ↑ CB1 and CB2 receptors and have been shown to reduce pain behavior in mice.5 • L.acidophilus, Bifidobateriam and oliofructoses • Weight loss by calorie restriction may ↓ CB1 receptors in the brain.2 • Long term and binge drinking () likely ↓ CB1 receptors.6 • Long term use of steroids may ↓ CB1 receptors in the brain.1

McPartland, et al., 2014 Alvhein, et al., 2012 Fowler, et al., 1999 Hogestatt, et al., 2005 Rousseaux, et al., 2007 Gonzalez et al., 2002 #TDVirtualSymposium 13

CBD & Cannabis Impact on ECS

Janice N. Bissex, MS, RDN

#TDVirtualSymposium 14

CBD & Cannabis: Impact on ECS

• CBD does not bind to receptors1 • ↓ FAAH ↑ anandamide (AEA)↑ CB1 activation • THC activates CB1 and CB2 receptors • THC binds tighter to CB1 receptors and has longer half life than AEA

• Pharmaceutical isolates do not have same impact. Whole plant = entourage/ensemble effect2

1. Sallaberry 2018 2. Russo 2011 #TDVirtualSymposium 15

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Cannabidiol (CBD) • Pain relief • Anti-inflammatory1 • Anti-bacterial1 • Anti-seizure2 • Anti-nausea • Anti-depressant • Anti-anxiety • Neuroprotective3,4 • Bone health5,6

1.Esposito 2013 2. Gupta 2016 3. National Academies of Sciences 2017 4. NIH 2003 5. Kogan 2015 6. Idris 2009 #TDVirtualSymposium 16

How Cannabis & CBD Relieve Pain • NAS 2017 report- conclusive evidence for ↓ pain • Inhibits release of pro-inflammatory molecules • Cannabis activates CB1 & CB2 receptors to ↓ pain signals • CBD • Inhibits FAAH↑AEA−>CB1 activation • ↓ transmission of pain signals • Activates receptors to ↓ pain perception

Manzanares 2006

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CBD & Mental Health

• CBD reduces fear and drug memory processes in PTSD, phobias, addiction1 • Anxiety and depression2 •↑AEA •↑serotonin •↑GABA inhibitory neurotransmitter •↓cortisol stress hormone • Synergy with SSRIs

Lee, 2017 Pretzsch, 2019 #TDVirtualSymposium 18

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Cannabis vs Hemp

• Both from L plant • Hemp contains < 0.3% THC • Cannabis contains up to 30% THC • Cannabis federally illegal • 33 states + DC allow medical and 11 states + allow medical and adult “recreational” use • Hemp production legalized in 2018 but no FDA decision on CBD Generally Recognized as Safe (GRAS) status

FDA.gov, 2020 #TDVirtualSymposium 19

Modes of Administration

•Sublingual tinctures •Topical Creams •Transdermal Patches •Capsules/softgels •Inhalation •Edibles •Suppositories •Raw juice

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Onset and Duration

Montemayor, M. Holistic Format/MethodCannabis Academy 2016 Onset(minutes) Duration (hours) Ingested (capsules, edibles, drinks) 30-120 6-12

Inhaled (vapor or smoke) 1-3 1-3 Sublingual (drops, lozenges, spray) 15-30 2-4

Topical (salves, roll-ons, creams) 30-60 2-4

Transdermal (patch, gels) 15-30 6-12

Suppositories 15-30 6-8

Montemayor, M. Holistic Cannabis Academy 2016 #TDVirtualSymposium 21

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Dosing: Start Low and Go Slow!

•Therapeutic ranges of CBD and THC are large •Individual personalization – keep journal •May take 2 weeks to see effect •THC tolerance – take a break!

Montemayor, M. Holistic Cannabis Academy 2016 #TDVirtualSymposium 22

Possible Drug Interactions

• May ↑ effect of some drugs • Be cautious taking meds contraindicated with grapefruit when ingesting cannabis1 - CYP450 enzyme system • Synergy with some meds (SSRIs) • Tricyclics: possible enhanced sedation, hypotension, tachycardia2 • Alcohol - THC may increase central nervous system (CNS) impairment3 • Check with cannabis practitioner

1. Grinspoon 2018 2. Devitt-Lee 2015 3. Kossen 2017 #TDVirtualSymposium 23

Potential Side Effects of CBD

• Vivid dreams • Fatigue • Low blood pressure • Dry mouth

2018 WHO Report on CBD:

“Across a number of controlled and open label trials of the potential therapeutic effects of CBD, it is generally well- tolerated with a good safety profile.” WHO: Cannabidiol (CBD): Critical Review Report 2018 #TDVirtualSymposium 24

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Potential Downside of Cannabis

Short term effects1 • Increased heart rate, distorted perception, loss of coordination, issues with memory and learning Cannabis Use Disorder (CUD) 2 • 8 to 12% of heavy users • More common with early age onset of use • Impairment effecting behavior, health, relationships • 4.2M in U.S. w CUD & 14.4M w alcohol use disorder3 • Cannabinoid hyperemesis syndrome Long term effect on cognition? Twin study4 • Psychotic disorders5,6,7 • Adolescent/heavy use may be risk for earlier onset • Correlation = causation? 1. NIDA 2019 2. Brezing 2018 3. SAMHSA.gov 4. Ross 2019 5. Garey, Child Mind Institute 6. Gage 2016 7. Di Forti 2019 #TDVirtualSymposium 25

Conclusions • The ECS is relatively new to most healthcare professionals and can contribute to homeostasis in the body • We can influence our ECS with lifestyle modifications, food, and plant-derived medicines like cannabis and CBD • It’s important to work with knowledgeable professionals when using plants as medicine

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References

1. DiMarzo V. 'Endocannabinoids' and other fatty acid derivatives with cannabimimetic properties: biochemisty and possible physiopathological relevance. Biochimica et Biophysica Act-Lipids and Lipid Metabolism. 1998;1392:153-175. 2. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Br J Pharmacol. 2006; 147(1):S163-171. 3. Adams R, Hunt M, Clark JH. Structure of Cannabidiol, a Product Isolated from the Marihuana Extract of Minnesota Wild Hemp. J Am Chem Soc. 1940;62(1):196-200. 4. Mechoulam, R. Marihuana: chemisty, pharmacology, metabolism and clinical effects. New York : Academic Press; 1973. 5. Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988:34:605-613. 6. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346: 561-564. 7. Devane W, Hanus L, Breuer A, Pertwee R, Stevenson L, Griffin G, Gibson D, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946-1949. 8. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabiniods. Nature. 1993; 365:61-65. 9. Stella N, Schweitzer, P, Piomelli D. A second endogenous cannabinoid that modulates long-term potentiation. Nature. 1997;388;773-778. 10.Piomelli DA, Giuffrida A, Calignano A, Rodriguez de Fronseca F. The endocannabiniod system as a target for therapeutic drugs. Trends Pharmacol. 2000;21(6):218-24. 11.Russo, E. Clinical Endocannabinoid Deficiency (CECD): Can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinology Letters. 2008; 29(2): 192-39.

12. Academies of Sciences, Engineering, Medicine. Report: The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington DC: The National Academy of Sciences Press, 2017. 13.Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997; 77:299- 318. 14.Onaivi ES. Commentary: functional neuronal CB2 cannabinoid receptors in the CNS. Cur Neuropharmacol. 2011; 9:205-208. 15.Atwood BK, Mackie K. CB2: a cannabinoid receptor with an identity crisis. Bri J Pharmacol. 2010;160:467-479. 16.Hauser AS, Chavali S, Masuho I, Jahn LJ, Martemyanov KA, Gloriam DE, Babu MM (January 2018). "Pharmacogenomics of GPCR Drug Targets". Cell. 172 (1–2): 41–54.e19. 17.Bisongo T, Petrocellis L, Marzo V. Enzyme with Many Bioactive Substrates. Possible Therapeutic Implications. Cur Pharm Design. 2002;8(7): 533-547.17. 18.Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathurai S, et al. Brain monoglyceride lipase participating in endocannabinoid inactivation. Proceedings of the National Academy of Sciences of the United States of America. 2002; 99(16): 10819-24. 19.Russo EB. Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes. Cannabis Cannabinoid Res. 2016;1(1):154–165. Published 2016 Jul 1. doi:10.1089/can.2016.0009 20.McPartland JM, Guy GW, DiMarzo V. Care and Feeding of the Endocannabinoid System: A Systemic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System. PLoS ONE. 2014; 9(3): e89566. 21.Alvhein AR, Malde MK, Osei-Hyiaman D, Lin YH, Pawlosky RJ. Dietary elevates endogenous 2-AG and anandamide and induces obesity. Obesity. 2012;20:1984-1994. 22.Fowler CJ, Janson U, Johnson RM, Wahlstrom G, Stenstrom A. Inhibition of anandamide hydrolysis by the enantiomers of , , and . Archives of Biochemistry and Biophysics. 1999;362;191-196. 23.Hogestatt ED, Josson BAG, Ermund A, Andersson DA, Bjork H. Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. J Bio Chem. 2005;280:31405-31412. 24.Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C. Lactobacillus acidophilus modulates intestinal pain and induces and cannabinoid receptors. Nat Med. 2007;13:35-37. 25.Gonzalez S, Cascio MG, Fernandez-Ruiz F, DiMarzo V. Changes in endocannabinoid contents in the brain of rats chronically exposed to , ethanol or . Brain Research. 2002;954:73-81.

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References

1. Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals.Ther Adv Psychopharmacol. 2012;2(6):241-254. 2. doi:10.1177/2045125312457586.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736954/. Accessed February 7, 2020. 3. Bonn-Miller MO, Loflin MJE, Thomas BF, et al. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017;318(17):1708-1709. 4. Bonn-Miller MO, ElSohly M, Loflin M, et al. Cannabis and cannabinoid drug development: Evaluating botanical versus single molecule approaches. Int Rev Psychiatry. 018;30(3):277-284. 5. Devitt-Lee, A. CBD-Drug Interactions: Role of Cytochrome P450. September 8, 2015https://www.projectcbd.org/medicine/cbd-drug-interactions/p450 Accessed March 24, 2020. 6. Di Forti M, Quattrone D, Freeman T, et al. The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study. The Lancet Psychiatry.2019:DOI:https://doi.org/10.1016/S2215-0366(19)30048-3 7. Drug scheduling. US Drug Enforcement Administration website. https://www.dea.gov/drug-scheduling. Accessed February 7, 2020. 8. Esposito G, Filippis DD, Cirillo C. Cannabidiol in inflammatory bowel diseases: a brief overview. Phytother Res. 2013;27(5):633-6. doi: 10.1002/ptr.4781.https://www.ncbi.nlm.nih.gov/pubmed/22815234. Accessed February 7, 2020. 9. Gage, SH, Hickman, M, Zammit, S. Association Between Cannabis and Psychosis: Epidemiologic Evidence. Biol Psychiatry. 2016 Apr 1;79(7):549-56. doi: 10.1016/j.biopsych.2015.08.001. Epub 2015 Aug 12. 10.Garey J. Marijuana and Psychosis. Child Mind Institute. https://childmind.org/article/marijuana-and-psychosis/ 11.Gupta, S. Why I changed my mind on weed. 2013;CNN Health https://www.cnn.com/2013/08/08/health/gupta-changed-mind-marijuana/index.html 12.Idris AI, Sophocleous A, Landao-Bassonga E, et al. Cannabinoid receptor type 1 protects against age-related osteoporosis by regulating osteoblast and adipocyte differentiation in marrow stromal cells. Cell Metab. 2009 Aug;10(2):139-47. doi: 10.1016/j.cmet.2009.07.006. 13.https://www.ncbi.nlm.nih.gov/pubmed/19656492. Accessed February 7, 2020. 14.https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd. Accesssed May 6, 2020 15.Kogan NM, Melamed E, Wasserman E, et al. Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts. J Bone Miner Res. 2015;30(10):1905-13. doi: 10.1002/jbmr.2513. Epub 2015 May 10. 16.Kossen, J. How does cannabis interact with other drugs? https://www.leafly.com/news/health/cannabis-cannabinoids-drug-interactions 17.Lee J, Bertoglio L, Guimarães F, Stevenson C. Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety‐related and substance abuse disorders. Br J Pharmacol. 2017174(19):3242-3256. doi: 10.1111/bph.13724. Epub 2017 Mar 9. 18.Manzanares J, Julian M, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol.2006;4(3):239– 257.doi:10.2174/157015906778019527.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430692/. Accessed February 7, 2020. 19.Montemayor, m. Dosage. Holistic Cannabis Academy website. http://holisticcannabisacademy.com/. Accessed February 7, 2019. 20.National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington, DC: The National Academies Press; 2017.https://doi.org/10.17226/24625. 21.National Institute of Drug Abuse. What is Marijuana? https://www.drugabuse.gov/publications/drugfacts/marijuana accessed April 7, 2020. 22.NIH U. S. National Library of Medicine: Cannabinoids as antioxidants and neuroprotectants. 2003 https://pubchem.ncbi.nlm.nih.gov/patent/US6630507 23.Pretzsch C, Freyberg J, Voinescu B, et.al. Effects of cannabidiol on brain excitation and inhibition systems; a randomised placebo-controlled single dose trial during magnetic resonance spectroscopy in adults with and without autism spectrum disorder. Neuropsychopharmacology. 2019; 44(8): 1398–1405. Published online 2019 Feb 6. doi: 10.1038/s41386-019-0333-8.https://www.ncbi.nlm.nih.gov/pubmed/30758329 .Accessed January 27, 2020. 24.Ross JM, Ellingson JM, Rhee SH, et. al. Investigating the causal effect of cannabis use on cognitive function with a quasi-experimental co-twin design. Drug Alcohol Depend. 2020; 206;107712 doi: 10.1016/j.drugalcdep.2019.107712. Epub 2019 Nov 2 25.Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163(7):1344-64. doi: 10.1111/j.1476-5381.2011.01238.x. 26.Sallaberry C, Astern L, The endocannabinoid system as a universal regulator. J of Young Investig. 2018 Accessed February 7, 2020 27.2018 Farm Bill. United States Senate Committee on Agriculture, Nutrition, & Forestry website.https://www.agriculture.senate.gov/2018-farm-bill. Accessed February 7, 2020. 28.World Health Organization. Cannabidiol (CBD): critical review report. https://www.who.int/medicines/access/controlled-substances/CannabidiolCriticalReview.pdf. Published June 2018. Accessed February 27, 2020.

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Questions? Janice Newell Bissex, MS, RDN Bonnie Johnson, MS, RDN

JannabisWellness.com Jannabis Wellness

JaniceBissex

[email protected] [email protected]

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