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<article xsi:noNamespaceSchemaLocation="http://jats.nlm.nih.gov/publishing/1.1/xsd/JATS-journalpublishing1-mathml3.xsd" dtd-version="1.1" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"><front><journal-meta><journal-id journal-id-type="publisher-id">HPR</journal-id><journal-title-group><journal-title>Health Psychology Research</journal-title></journal-title-group><issn>TBA</issn><eissn>2420-8124</eissn><publisher><publisher-name>Health Psychology Research</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.52965/001c.35848</article-id><article-categories><subj-group subj-group-type="heading"><subject>General</subject></subj-group></article-categories><title>Cannabinoids and Their Role in Chronic Pain Treatment: Current   Concepts and a Comprehensive Review</title><url>https://healthpr.org/journal/HPR/10/4/10.52965/001c.35848</url><author>ShehataIslam,HashimAhmed,ElsaeidyAhmed Saad,NairAnagha,UritsIvan,ViswanathOmar,Alan D. KayeAlan,HabibMarian</author><pub-date pub-type="publication-year"><year>2022</year></pub-date><volume>10</volume><issue>4</issue><history><date date-type="pub"><published-time>2022-10-03</published-time></date></history><abstract>For decades, chronic pain was managed with an almost conventional approach of using a wide range of analgesic spectrum, surgical approaches and complex interventional pain techniques to modulate or even interrupt pain pathways. These different approaches carry many pharmacological hazards together with the lack of efficacy and safety of many interventional and surgical management techniques for chronic pain have mandated searching for other effective therapies including alternative treatments. Cannabinoids are naturally occurring substances that are derived from Cannabis sativa L. The usage of cannabinoids and their related synthetic chemical compounds has emerged as a choice in the management of different chronic pain conditions is being evaluated, however, the efficacy is still not consistently established. In the present investigation, therefore, we discuss the different aspects related to cannabinoids and their implications in the management of chronic pain conditions. This review will also discuss the safety profile of the cannabinoids together with the legal considerations that hinder their use in different countries.</abstract><keywords>Hurghada General Hospital, Department of Cardiology, Hurghada, Egypt</keywords></article-meta></front><body/><back><ref-list><ref id="B1" content-type="article"><label>1</label><element-citation publication-type="journal"><p>1. Fine PG. Long-term consequences of chronic pain: mounting evidence for pain as a neurological disease and parallels with other chronic disease states. Pain Med. 2011;12(7):996-1004. doi:10.1111/j.1526-4637.2011.01187.x2. Raffaeli W, Arnaudo E. Pain as a disease: an overview. J Pain Res. 2017;10:2003-2008. doi:10.2147/JPR.S1388643. Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults - United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67(36):1001-1006. doi:10.15585/mmwr.mm6736a24. Treede RD, Rief W, Barke A, et al. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003-1007. doi:10.1097/j.pain.00000000000001605. Beal BR, Wallace MS. An Overview of Pharmacologic Management of Chronic Pain. Med Clin North Am. 2016;100(1):65-79. doi:10.1016/j.mcina.2015.08.0066. Hylands-White N, Duarte RV, Raphael JH. An overview of treatment approaches for chronic pain management. Rheumatol Int. 2017;37(1):29-42. doi:10.1007/s00296-016-3481-87. Graham DY, Opekun AR, Willingham FF, Qureshi WA. Visible small-intestinal mucosal injury in chronic NSAID users. Clin Gastroenterol Hepatol. 2005;3(1):55-59. doi:10.1016/s1542-3565(04)00603-28. Castellsague J, Pisa F, Rosolen V, et al. Risk of upper gastrointestinal complications in a cohort of users of nimesulide and other nonsteroidal anti-inflammatory drugs in Friuli Venezia Giulia, Italy. Pharmacoepidemiol Drug Saf. 2013;22(4):365-375. doi:10.1002/pds.33859. McDowell K, Clements JN. How can NSAIDs harm cardiovascular and renal function? JAAPA. 2014;27(4):12-15. doi:10.1097/01.JAA.0000444738.62411.8310. Degenhardt L, Charlson F, Mathers B, et al. The global epidemiology and burden of opioid dependence: results from the global burden of disease 2010 study. Addiction. 2014;109(8):1320-1333. doi:10.1111/add.1255111. Volkow ND, Icaza MEM, Poznyak V, Saxena S, Gerra G, UNODC-WHO Informal Scientific Network. Addressing the opioid crisis globally. World Psychiatry. 2019;18(2):231-232. doi:10.1002/wps.2063312. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 Suppl):S105-20.13. Vowles KE, McEntee ML, Julnes PS, Frohe T, Ney JP, van der Goes DN. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain. 2015;156(4):569-576. doi:10.1097/01.j.pain.0000460357.01998.f114. Lucas P. Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain. J Psychoactive Drugs. 2012;44(2):125-133. doi:10.1080/02791072.2012.68462415. Bonini SA, Premoli M, Tambaro S, et al. Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history. J Ethnopharmacol. 2018;227:300-315. doi:10.1016/j.jep.2018.09.00416. Lynch ME. Cannabinoids in the management of chronic pain: a front line clinical perspective. J Basic Clin Physiol Pharmacol. 2016;27(3):189-191. doi:10.1515/jbcpp-2015-005917. Fitzcharles MA, Baerwald C, Ablin J, Hauser W. Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): a systematic review of randomized controlled trials. Schmerz. 2016;30(1):47-61. doi:10.1007/s00482-015-0084-318. Hauser W, Petzke F, Fitzcharles MA. Efficacy, tolerability and safety of cannabis-based medicines for chronic pain management - an overview of systematic reviews. Eur J Pain. 2018;22(3):455-470. doi:10.1002/ejp.111819. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015;313(24):2456-2473. doi:10.1001/jama.2015.635820. Chaves C, Bittencourt PCT, Pelegrini A. Ingestion of a THC-Rich Cannabis Oil in People with Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Pain Med. 2020;21(10):2212-2218. doi:10.1093/pm/pnaa30321. Vickery AW, Finch PM. Cannabis: are there any benefits? Intern Med J. 2020;50(11):1326-1332. doi:10.1111/imj.1505222. Almog S, Aharon-Peretz J, Vulfsons S, et al. The pharmacokinetics, efficacy, and safety of a novel selective-dose cannabis inhaler in patients with chronic pain: a randomized, double-blinded, placebo-controlled trial. Eur J Pain. 2020;24(8):1505-1516. doi:10.1002/ejp.160523. Hosseini A, McLachlan AJ, Lickliter JD. A phase I trial of the safety, tolerability and pharmacokinetics of cannabidiol administered as single-dose oil solution and single and multiple doses of a sublingual wafer in healthy volunteers. Br J Clin Pharmacol. 2021;87(4):2070-2077. doi:10.1111/bcp.1461724. Izgelov D, Davidson E, Barasch D, Regev A, Domb AJ, Hoffman A. Pharmacokinetic investigation of synthetic cannabidiol oral formulations in healthy volunteers. Eur J Pharm Biopharm. 2020;154:108-115. doi:10.1016/j.ejpb.2020.06.02125. Perkins D, Butler J, Ong K, et al. A Phase 1, Randomised, Placebo-Controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Fed Healthy Volunteers. Eur J Drug Metab Pharmacokinet. 2020;45(5):575-586. doi:10.1007/s13318-020-00624-626. Vazquez M, Guevara N, Maldonado C, Guido PC, Schaiquevich P. Potential Pharmacokinetic Drug-Drug Interactions between Cannabinoids and Drugs Used for Chronic Pain. Biomed Res Int. 2020;2020:3902740. doi:10.1155/2020/390274027. Zou S, Kumar U. Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci. 2018;19(3). doi:10.3390/ijms1903083328. Starowicz K, Finn DP. Cannabinoids and Pain: Sites and Mechanisms of Action. Adv Pharmacol. 2017;80:437-475. doi:10.1016/bs.apha.2017.05.00329. Silver RJ. The Endocannabinoid System of Animals. Animals (Basel). 2019;9(9). doi:10.3390/ani909068630. Chavez AE, Chiu CQ, Castillo PE. TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus. Nat Neurosci. 2010;13(12):1511-1518. doi:10.1038/nn.268431. Demuth DG, Molleman A. Cannabinoid signalling. Life Sci. 2006;78(6):549-563. doi:10.1016/j.lfs.2005.05.05532. Turcotte C, Blanchet MR, Laviolette M, Flamand N. The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci. 2016;73(23):4449-4470. doi:10.1007/s00018-016-2300-433. Schmitz K, Mangels N, Haussler A, Ferreiros N, Fleming I, Tegeder I. Pro-inflammatory obesity in aged cannabinoid-2 receptor-deficient mice. Int J Obes (Lond). 2016;40(2):366-379. doi:10.1038/ijo.2015.16934. Singh UP, Singh NP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS. Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(-/-) mice by attenuating the activation of T cells and promoting their apoptosis. Toxicol Appl Pharmacol. 2012;258(2):256-267. doi:10.1016/j.taap.2011.11.00535. Shang Y, Tang Y. The central cannabinoid receptor type-2 (CB2) and chronic pain. Int J Neurosci. 2017;127(9):812-823. doi:10.1080/00207454.2016.125799236. Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009;89(1):309-380. doi:10.1152/physrev.00019.200837. Castillo PE, Younts TJ, Chavez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron. 2012;76(1):70-81. doi:10.1016/j.neuron.2012.09.02038. Staton PC, Hatcher JP, Walker DJ, et al. The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain. Pain. 2008;139(1):225-236. doi:10.1016/j.pain.2008.04.00639. Huang SM, Bisogno T, Petros TJ, et al. Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain. J Biol Chem. 2001;276(46):42639-42644. doi:10.1074/jbc.M10735120040. Scavone JL, Sterling RC, Van Bockstaele EJ. Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal. Neuroscience. 2013;248:637-654. doi:10.1016/j.neuroscience.2013.04.03441. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005;30(8):1037-1043. doi:10.1007/s1064-005-6978-142. O&amp;rsquo;Sullivan SE. An update on PPAR activation by cannabinoids. Br J Pharmacol. 2016;173(12):1899-1910. doi:10.1111/bph.1349743. Bakas T, van Nieuwenhuijzen PS, Devenish SO, McGregor IS, Arnold JC, Chebib M. The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABAA receptors. Pharmacol Res. 2017;119:358-370. doi:10.1016/j.phrs.2017.02.02244. Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog Chem Org Nat Prod. 2017;103:103-131. doi:10.1007/978-3-319-45541-9_445. Iffland K, Grotenhermen F. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis Cannabinoid Res. 2017;2(1):139-154. doi:10.1089/can.2016.003446. Atalay S, Jarocka-Karpowicz I, Skrzydlewska E. Antioxidative and Anti-Inflammatory Properties of Cannabidiol. Antioxidants (Basel). 2019;9(1). doi:10.3390/antiox901002147. Ke P, Shao BZ, Xu ZQ, et al. Activation of Cannabinoid Receptor 2 Ameliorates DSS-Induced Colitis through Inhibiting NLRP3 Inflammasome in Macrophages. PLoS One. 2016;11(9):e0155076. doi:10.1371/journal.pone.015507648. Shao BZ, Wei W, Ke P, Xu ZQ, Zhou JX, Liu C. Activating cannabinoid receptor 2 alleviates pathogenesis of experimental autoimmune encephalomyelitis via activation of autophagy and inhibiting NLRP3 inflammasome. CNS Neurosci Ther. 2014;20(12):1021-1028. doi:10.1111/cns.1234949. Shi CS, Shenderov K, Huang NN, et al. Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012;13(3):255-263. doi:10.1038/ni.221550. Wirth PW, Watson ES, ElSohly M, Turner CE, Murphy JC. Anti-inflammatory properties of cannabichromene. Life Sci. 1980;26(23):1991-1995. doi:10.1016/0024-3205(80)90631-151. Zurier RB, Burstein SH. Cannabinoids, inflammation, and fibrosis. FASEB J. 2016;30(11):3682-3689. doi:10.1096/fj.201600646R52. Do Y, McKallip RJ, Nagarkatti M, Nagarkatti PS. Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation. J Immunol. 2004;173(4):2373-2382. doi:10.4049/jimmunol.173.4.237353. Lu T, Newton C, Perkins I, Friedman H, Klein TW. Cannabinoid treatment suppresses the T-helper cell-polarizing function of mouse dendritic cells stimulated with Legionella pneumophila infection. J Pharmacol Exp Ther. 2006;319(1):269-276. doi:10.1124/jpet.106.10838154. Parker J, Atez F, Rossetti RG, Skulas A, Patel R, Zurier RB. Suppression of human macrophage interleukin-6 by a nonpsychoactive cannabinoid acid. Rheumatol Int. 2008;28(7):631-635. doi:10.1007/s00296-007-0489-055. Puffenbarger RA, Boothe AC, Cabral GA. Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia. 2000;29(1):58-69.56. Fiani B, Sarhadi KJ, Soula M, Zafar A, Quadri SA. Current application of cannabidiol (CBD) in the management and treatment of neurological disorders. Neurol Sci. 2020;41(11):3085-3098. doi:10.1007/s10072-020-04514-257. Weizman L, Dayan L, Brill S, et al. Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity. Neurology. 2018;91(14):e1285-e1294. doi:10.1212/WNL.00000000000629358. Xu DH, Cullen BD, Tang M, Fang Y. The Effectiveness of Topical Cannabidiol Oil in Symptomatic Relief of Peripheral Neuropathy of the Lower Extremities. Curr Pharm Biotechnol. 2020;21(5):390-402. doi:10.2174/138920102066619120211153459. van Amerongen G, Kanhai K, Baakman AC, et al. Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Delta9-tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis. Clin Ther. 2018;40(9):1467-1482. doi:10.1016/j.clinthera.2017.01.01660. Lichtman AH, Lux EA, McQuade R, et al. Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain. J Pain Symptom Manage. 2018;55(2):179-188 e1. doi:10.1016/j.jpainsymman.2017.09.00161. Wright P, Walsh Z, Margolese S, et al. Canadian clinical practice guidelines for the use of plant-based cannabis and cannabinoid-based products in the management of chronic non-cancer pain and co-occurring conditions: protocol for a systematic literature review. BMJ Open. 2020;10(5):e036114. doi:10.1136/bmjopen-2019-03611462. Berger AA, Keefe J, Winnick A, et al. Cannabis and cannabidiol (CBD) for the treatment of fibromyalgia. Best Pract Res Clin Anaesthesiol. 2020;34(3):617-631. doi:10.1016/j.bpa.2020.08.01063. van de Donk T, Niesters M, Kowal MA, Olofsen E, Dahan A, van Velzen M. An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain. 2019;160(4):860-869. doi:10.1097/j.pain.000000000000146464. Akram H, Mokrysz C, Curran HV. What are the psychological effects of using synthetic cannabinoids? A systematic review. J Psychopharmacol. 2019;33:271-283. doi:10.1177/026988111982659265. Karschner EL, Darwin WD, McMahon RP, et al. Subjective and physiological effects after controlled sativex and oral THC administration. Clin Pharmacol Ther. 2011;89:400-407. doi:10.1038/clpt.2010.31866. Bedi G, Cooper ZD, Haney M. Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers. Addict Biol. 2013;18:872-881. doi:10.1111/j.1369-1600.2011.00427.x67. Jicha CJ, Lofwall MR, Nuzzo PA, Babalonis S, Elayi SC, Walsh SL. Safety of oral dronabinol during opioid withdrawal in humans. Drug Alcohol Depend. 2015;157:179-183. doi:10.1016/j.drugalcdep.2015.09.03168. Hemachandra D, McKetin R, Cherbuin N, Anstey KJ. Heavy cannabis users at elevated risk of stroke: evidence from a general population survey. Aust N Z J Public Health. 2016;40:226-230. doi:10.1111/1753-6405.1247769. Wolff V, Lauer V, Rouyer O, et al. Cannabis use, ischemic stroke, and multifocal intracranial vasoconstriction: a prospective study in 48 consecutive young patients. Stroke. 2011;42:1778-1780. doi:10.1161/STROKEAHA.110.61091570. Ravi D, Ghasemiesfe M, Korenstein D, Cascino T, Keyhani S. Associations between marijuana use and cardiovascular risk factors and outcomes a systematic review. Ann Intern Med. 2018;168:187-194. doi:10.7326/M17-154871. Gilron I, Blyth FM, Degenhardt L, et al. Risks of harm with cannabinoids, cannabis, and cannabis-based medicine for pain management relevant to patients receiving pain treatment: protocol for an overview of systematic reviews. Pain Rep. 2019;4. doi:10.1097/PR9.000000000000074272. Korantzopoulos P, Liu T, Papaioannides D, Li G, Goudevenos JA. Atrial fibrillation and marijuana smoking. Int J Clin Pract. 2008;62:308-313. doi:10.1111/j.1742-1241.2007.01505.x73. Coughlin PA, Mavor AID. Arterial Consequences of Recreational Drug Use. Eur J Vasc Endovasc Surg. 2006;32:389-396. doi:10.1016/j.ejvs.2006.03.00374. Ghasemiesfe M, Ravi D, Vali M, et al. Marijuana use, respiratory symptoms, and pulmonary function: a systematic review and meta-analysis. Ann Intern Med. 2018;169:106-115. doi:10.7326/M18-052275. Martinasek MP, McGrogan JB, Maysonet A. A systematic review of the respiratory effects of inhalational marijuana. Respir Care. 2016;61:1543-1551. doi:10.4187/respcare.0484676. Mehra R, Moore BA, Crothers K, Tetrault J, Fiellin DA. The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med. 2006;166:1359-1367. doi:10.1001/archinte.166.13.135977. Tan C, Hatam N, Treasure T. Bullous Disease of the Lung and Cannabis Smoking: Insufficient Evidence for a Causative Link. J R Soc Med. 2006;99:77-80. doi:10.1177/01410768060990022078. Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med. 2007;167:221-228. doi:10.1001/archinte.167.3.22179. Borges G, Bagge CL, Orozco R. A literature review and meta-analyses of cannabis use and suicidality. J Affect Disord. 2016;195:63-74. doi:10.1016/j.jad.2016.02.00780. Gobbi G, Atkin T, Zytynski T, et al. Association of Cannabis Use in Adolescence and Risk of Depression, Anxiety, and Suicidality in Young Adulthood: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2019;76:426-434. doi:10.1001/jamapsychiatry.2018.450081. Amar MB, Potvin S. Cannabis and Psychosis: what is the Link? J Psychoact Drugs. 2007;39:131-142. doi:10.1080/02791072.2007.1039987182. Large M, Sharma S, Compton MT, Slade T, Nielssen O. Cannabis use and earlier onset of psychosis: a systematic meta-analysis. Arch Gen Psychiatry. 2011;68:555-561. doi:10.1001/archgenpsychiatry.2011.583. Myles N, Newall H, Nielssen O, Large M. The Association between Cannabis Use and Earlier Age at Onset of Schizophrenia and other Psychoses: Meta-analysis of Possible Confounding Factors. Curr Pharm Des. 2012;18:5055-5069. doi:10.2174/13816121280288481684. Ragazzi TCC, Shuhama R, Menezes PR, Del-Ben CM. Cannabis use as a risk factor for psychotic-like experiences: a systematic review of non-clinical populations evaluated with the Community Assessment of Psychic Experiences. J Early Interv. 2018;12:1013-1023. doi:10.1111/eip.1269385. Marconi A, Di Forti M, Lewis CM, Murray RM, Vassos E. Meta-Analysis of the association between the level of cannabis use and risk of psychosis. Schizophr Bull. 2016;42:1262-1269. doi:10.1093/schbul/sbw00386. Kedzior KK, Laeber LT. A positive association between anxiety disorders and cannabis use or cannabis use disorders in the general population- a meta-analysis of 31 studies. BMC Psychiatry. 2014;14. doi:10.1186/1471-244X-14-13687. Ganzer F, Br&amp;ouml;ning S, Kraft S, Sack PM, Thomasius R. Weighing the Evidence: A Systematic Review on Long-Term Neurocognitive Effects of Cannabis Use in Abstinent Adolescents and Adults. Neuropsychol Rev. 2016;26:186-222. doi:10.1007/s11065-016-9316-288. Grant I, Gonzalez R, Carey CL, Natarajan L, Wolfson T. Non-acute (residual) neurocognitive effects of cannabis use: a meta-analytic study. J Int Neuropsychol Soc. 2003;9:679-689. doi:10.1017/S135561770395001689. Rabin RA, Zakzanis KK, George TP. The effects of cannabis use on neurocognition in schizophrenia: a meta-analysis. Schizophr Res. 2011;128:111-116. doi:10.1016/j.schres.2011.02.01790. Scott JC, Slomiak ST, Jones JD, Rosen AFG, Moore TM, Gur RC. Association of Cannabis With Cognitive Functioning in Adolescents and Young Adults A Systematic Review and Meta-analysis. JAMA Psychiatry. 2018;75:585-595. doi:10.1001/jamapsychiatry.2018.033591. Oomen PP, Van Hell HH, Bossong MG. The acute effects of cannabis on human executive function. Behav Pharmacol. 2018;29:605-616. doi:10.1097/FBP.00000000000042692. Bogaty SER, Lee RSC, Hickie IB, Hermens DF. Meta-analysis of neurocognition in young psychosis patients with current cannabis use. J Psychiatr Res. 2018;99:22-32. doi:10.1016/j.jpsychires.2018.01.01093. Schoeler T, Monk A, Sami MB, et al. Continued versus discontinued cannabis use in patients with psychosis: a systematic review and meta-analysis. Lancet Psychiatry. 2016;3:215-225. doi:10.1016/S2215-0366(15)00363-694. Platt B, O&amp;rsquo;Driscoll C, Curran VH, Rendell PG, Kamboj SK. The effects of licit and illicit recreational drugs on prospective memory: a meta-analytic review. Psychopharmacology. 2019;236:1131-1143. doi:10.1007/s00213-019-05245-995. Schreiner AM, Dunn ME. Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis. Exp Clin Psychopharmacol. 2012;20:420-429. doi:10.1037/a002911796. Gurney J, Shaw C, Stanley J, Signal V, Sarfati D. Cannabis exposure and risk of testicular cancer: a systematic review and meta-analysis. BMC Cancer. 2015;15. doi:10.1186/s12885-015-1905-697. Ghasemiesfe M, Barrow B, Leonard S, Keyhani S, Korenstein D. Association between Marijuana Use and Risk of Cancer: A Systematic Review and Meta-analysis. JAMA Network Open. 2019;2:1-15. doi:10.1001/jamanetworkopen.2019.1631898. Calabria B, Degenhardt L, Hall W, Lynskey M. Does cannabis use increase the risk of death? Systematic review of epidemiological evidence on adverse effects of cannabis use. Drug Alcohol Rev. 2010;29:318-330. doi:10.1111/j.1465-3362.2009.00149.x99. Hashibe M, Straif K, Tashkin DP, Morgenstern H, Greenland S, Zhang ZF. Epidemiologic review of marijuana use and cancer risk. Alcohol. 2005;35:265-275. doi:10.1016/j.alcohol.2005.04.008100. Huang YHJ, Zhang ZF, Tashkin DP, Feng B, Straif K, Hashibe M. An epidemiologic review of marijuana and cancer: an update. Cancer Epidemiol Biomark Prev. 2015;24:15-31. doi:10.1158/1055-9965.EPI-14-1026101. Sharapova SR, Phillips E, Sirocco K, Kaminski JW, Leeb RT, Rolle I. Effects of prenatal marijuana exposure on neuropsychological outcomes in children aged 1-11 years: a systematic review. Paediatr Perinat Epidemiol. 2018;32:512-532. doi:10.1111/ppe.12505102. Conner SN, Bedell V, Lipsey K, Macones GA, Cahill AG, Tuuli MG. Maternal Marijuana Use and Adverse Neonatal Outcomes: A Systematic Review and Meta-analysis. Obstet Gynecol. 2016;128:713-723. doi:10.1097/AOG.0000000000001649103. Gunn JKL, Rosales CB, Center KE, et al. Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis. BMJ Open. 2016;6:1-8. doi:10.1136/bmjopen-2015-009986104. Tournebize J, Gibaja V, Kahn JP. Acute effects of synthetic cannabinoids: update 2015. Subst Abuse. 2017;38:344-366. doi:10.1080/08897077.2016.1219438105. Courts J, Maskill V, Gray A, Glue P. Signs and symptoms associated with synthetic cannabinoid toxicity: systematic review. Australas Psychiatry. 2016;24:598-601. doi:10.1177/1039856216663733106. Haden M, Archer JRH, Dargan PI, Wood DM. MDMB-CHMICA: Availability, Patterns of Use, and Toxicity Associated With This Novel Psychoactive Substance. Subst Use Misuse. 2017;52:223-232. doi:10.1080/10826084.2016.1223692107. Tait RJ, Caldicott D, Mountain D, Hill SL, Lenton S. A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment. Clin Toxicol. 2016;54:1-13. doi:10.3109/15563650.2015.1110590108. Mansoor K, Kheetan M, Shahnawaz S, et al. Systematic review of nephrotoxicity of drugs of abuse, 2005-2016. BMC Nephrology. 2017;18:1-15. doi:10.1186/s12882-017-0794-0109. Panlilio LV, Goldberg SR, Justinova Z. Cannabinoid Abuse and Addiction: Clinical and Preclinical Findings. Clin Pharmacol Ther. 2015;97:616-627. doi:10.1002/cpt.118110. Budney AJ, Roffman R, Stephens RS, Walker D. Marijuana dependence and its treatment. Addict Sci Clin Pract. 2007;4:4-16. doi:10.1151/ASCP07414111. Ramesh D, Schlosburg JE, Wiebelhaus JM, Lichtman AH. Marijuana dependence: not just smoke and mirrors. ILAR Journal. 2011;52:295-308. doi:10.1093/ilar.52.3.295112. Patel J, Marwaha R. Cannabis Use Disorder. In: Clinical Handbook of Adolescent Addiction. ; 2019:202-212.113. Degenhardt L, Ferrari AJ, Calabria B, et al. The Global Epidemiology and Contribution of Cannabis Use and Dependence to the Global Burden of Disease: Results from the GBD 2010 Study. PLoS ONE. 2013;8:9-37. doi:10.1371/journal.pone.0076635114. Freeman TP, Hindocha C, Baio G, et al. Europe PMC Funders Group Cannabidiol for the treatment of cannabis use disorder: Phase IIa double-blind placebo-controlled randomised adaptive Bayesian dose-finding trial. 2021;7:865-874. doi:10.1016/S2215-0366(20)30290-X.Cannabidiol115. Gilbert DG, Rabinovich NE, McDaniel JT. Nicotine patch for cannabis withdrawal symptom relief: a randomized controlled trial. Psychopharmacology. 2020;237:1507-1519. doi:10.1007/s00213-020-05476-1116. Sherman BJ, Caruso MA, McRae-Clark AL. Exogenous progesterone for cannabis withdrawal in women: feasibility trial of a novel multimodal methodology. Pharmacol Biochem Behav. 2019;179:22-26. doi:10.1016/j.pbb.2019.01.008117. Allsop DJ, Copeland J, Lintzeris N, et al. Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiatry. 2014;71:281-291. doi:10.1001/jamapsychiatry.2013.3947118. Haney M, Hart CL, Vosburg SK, Comer SD, Reed SC, Foltin RW. Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse. Psychopharmacology. 2008;197:157-168. doi:10.1007/s00213-007-1020-8119. Walther L, Gantner A, Heinz A, Majic T. Evidenzbasierte Behandlungsoptionen der Cannabisabh&amp;auml;ngigkeit. Deutsches Arzteblatt International. 2016;113:653-659. doi:10.3238/arztebl.2016.0653120. Zvonarev V, Fatuki TA, Tregubenko P. The Public Health Concerns of Marijuana Legalization: An Overview of Current Trends. Cureus. 2019;11. doi:10.7759/cureus.5806121. Turner AR, Agrawal S. Marijuana. In: StatPearls. StatPearls Publishing; 2020.122. Breijyeh Z, Jubeh B, Bufo SA, Karaman R, Scrano L. Cannabis: A Toxin-Producing Plant with Potential Therapeutic Uses. Toxins. 2021;13:1-2. doi:10.3390/toxins13020117123. Bahji A, Stephenson C. International perspectives on the implications of cannabis legalization: a systematic review &amp;amp; thematic analysis. Int J Environ Res Public Health. 2019;16. doi:10.3390/ijerph16173095124. Hall W, Lynskey M. Assessing the public health impacts of legalizing recreational cannabis use: the US experience. World Psychiatry. 2020;19:179-186. doi:10.1002/wps.20735125. Leyton M. Cannabis legalization: Did we make a mistake? update 2019. J Psychiatry Neurosci. 2019;44:291-293. doi:10.1503/jpn.190136126. Di Forti M. To legalize or not to legalize cannabis, that is the question! World Psychiatry. 2020;19:188-189. doi:10.1002/wps.20737</p><pub-id pub-id-type="doi"/></element-citation></ref></ref-list></back></article>
