\\n\\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\\n\\nLaunching 2021
\\n\\nArtificial Intelligence, ISSN 2633-1403
\\n\\nVeterinary Medicine and Science, ISSN 2632-0517
\\n\\nBiochemistry, ISSN 2632-0983
\\n\\nBiomedical Engineering, ISSN 2631-5343
\\n\\nInfectious Diseases, ISSN 2631-6188
\\n\\nPhysiology (Coming Soon)
\\n\\nDentistry (Coming Soon)
\\n\\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\\n\\nNote: Edited in October 2021
\\n"}]',published:!0,mainMedia:{caption:"",originalUrl:"/media/original/132"}},components:[{type:"htmlEditorComponent",content:'With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\nDesigned to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\nAfter a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\nOur innovative Book Series format brings you:
\n\nIntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\nIntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
\n\nLaunching 2021
\n\nArtificial Intelligence, ISSN 2633-1403
\n\nVeterinary Medicine and Science, ISSN 2632-0517
\n\nBiochemistry, ISSN 2632-0983
\n\nBiomedical Engineering, ISSN 2631-5343
\n\nInfectious Diseases, ISSN 2631-6188
\n\nPhysiology (Coming Soon)
\n\nDentistry (Coming Soon)
\n\nWe invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\nNote: Edited in October 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"9853",leadTitle:null,fullTitle:"Connectivity and Functional Specialization in the Brain",title:"Connectivity and Functional Specialization in the Brain",subtitle:null,reviewType:"peer-reviewed",abstract:"‘Connectivity and Functional Specialization in the Brain’ is a topic that describes nerve cells in terms of their anatomical and functional connections. The term connectome refers to a comprehensive map of neural connections, like a wiring diagram of an organism’s nervous system. Connectomics, the study of connectomes, can be applied to individual neurons and their synaptic connections, as well as to connections between neuronal populations or to functional and structural connectivity of different brain regions. This book addresses neural connectivity at these various scales in health and disease. The chapters review novel findings related to neuroanatomy and cell biology, neurophysiology, neural plasticity, changes of connectivity in neurological disorders, and sensory system connectivity. The book provides the reader with an overview of the current state-of-the-art of research of neural connectivity and focuses on the most important evidence-based developments in this area. Individual chapters focus on recent advances in specific areas of neural connectivity and in different brain regions. All chapters represent recent contributions to the rapidly developing field of neural connectivity.",isbn:"978-1-83962-797-2",printIsbn:"978-1-83962-796-5",pdfIsbn:"978-1-83962-798-9",doi:"10.5772/intechopen.87662",price:119,priceEur:129,priceUsd:155,slug:"connectivity-and-functional-specialization-in-the-brain",numberOfPages:174,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"79f611488f3217579b5c84978f870863",bookSignature:"Thomas Heinbockel and Yongxia Zhou",publishedDate:"June 2nd 2021",coverURL:"https://cdn.intechopen.com/books/images_new/9853.jpg",numberOfDownloads:2390,numberOfWosCitations:3,numberOfCrossrefCitations:3,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:5,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:11,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 17th 2020",dateEndSecondStepPublish:"July 8th 2020",dateEndThirdStepPublish:"September 6th 2020",dateEndFourthStepPublish:"November 25th 2020",dateEndFifthStepPublish:"January 24th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"70569",title:"Dr.",name:"Thomas",middleName:null,surname:"Heinbockel",slug:"thomas-heinbockel",fullName:"Thomas Heinbockel",profilePictureURL:"https://mts.intechopen.com/storage/users/70569/images/system/70569.jfif",biography:"Thomas Heinbockel, Ph.D., is a professor and interim chair, Department of Anatomy, Howard University College of Medicine, Washington, DC. He holds an adjunct faculty position in both the Department of Anatomy & Neurobiology and the Department of Physiology, University of Maryland School of Medicine. Dr. Heinbockel studied biology at the Philipps-University, Germany. His studies of the brain started during his MS thesis work at the Max Planck Institute for Behavioral Physiology, Germany. Dr. Heinbockel earned a Ph.D. in Neuroscience at the University of Arizona, USA. After graduating, he worked as a research associate at the Institute of Physiology, Otto-von-Guericke University, Germany. Dr. Heinbockelʿs research is focused on understanding how the brain processes information as it relates to neurological and psychiatric disorders. His laboratory at Howard University concentrates on foundational and translational topics such as drug development, organization of the olfactory and limbic systems, and neural signaling and synaptic transmission in the central nervous system.",institutionString:"Howard University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"10",totalChapterViews:"0",totalEditedBooks:"8",institution:{name:"Howard University",institutionURL:null,country:{name:"United States of America"}}}],equalEditorOne:{id:"259308",title:"Dr.",name:"Yongxia",middleName:null,surname:"Zhou",slug:"yongxia-zhou",fullName:"Yongxia Zhou",profilePictureURL:"https://mts.intechopen.com/storage/users/259308/images/system/259308.jpeg",biography:"Yongxia Zhou obtained a Ph.D. in Biomedical Imaging from the University of Southern California. Her research interest is radiology and neuroscience technology and application. She had been trained as an imaging scientist at several prestigious institutes including Columbia University, the University of Pennsylvania, and the National Institutes of Health (NIH). Her research focuses on multi-modal neuroimaging integration such as MRI/PET and EEG/MEG instrumentation to make the best use of multiple modalities for better interpretation of underlying disease mechanisms. She is the author and editor of more than twelve books for well-known publishers including IntechOpen and Nova Science. She has published more than 100 papers and abstracts in many reputed international journals and conferences and served as reviewer and editor for several academic associations.",institutionString:"University of Southern California",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"4",institution:{name:"University of Southern California",institutionURL:null,country:{name:"United States of America"}}},equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"215",title:"Neurophysiology",slug:"neurophysiology"}],chapters:[{id:"74798",title:"Cytokine Profile as a Marker of Cell Damage and Immune Dysfunction after Spinal Cord Injury",doi:"10.5772/intechopen.95614",slug:"cytokine-profile-as-a-marker-of-cell-damage-and-immune-dysfunction-after-spinal-cord-injury",totalDownloads:435,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The study reviews findings of the recent experiments designed to investigate cytokine profile after a spinal cord injury. The role of key cytokines was assessed in the formation of cellular response to trauma. The specific immunopathogenic interaction of the nervous and immune systems in the immediate and chronic post-traumatic periods is summarized. The practicality of a step-by-step approach to assessing the cytokine profile in spinal cord injury is shown, the need to take into account the combination of pathogenetic and protective components in the implementation regulatory effects of individual cytokines, their integration into regenerative processes in the damaged spinal cord, which allows a rational approach to the organization of the treatment process and the development of new medicines.",signatures:"Georgii Telegin, Aleksandr Chernov, Alexey Belogurov, Irina Balmasova, Nikolai Konovalov and Aleksandr Gabibov",downloadPdfUrl:"/chapter/pdf-download/74798",previewPdfUrl:"/chapter/pdf-preview/74798",authors:[{id:"332132",title:"Dr.",name:"Georgii",surname:"Telegin",slug:"georgii-telegin",fullName:"Georgii Telegin"},{id:"332136",title:"Dr.",name:"Aleksandr",surname:"Gabibov",slug:"aleksandr-gabibov",fullName:"Aleksandr Gabibov"},{id:"332504",title:"Dr.",name:"Aleksandr",surname:"Chernov",slug:"aleksandr-chernov",fullName:"Aleksandr Chernov"},{id:"332506",title:"Dr.",name:"Nikolay",surname:"Konovalov",slug:"nikolay-konovalov",fullName:"Nikolay Konovalov"},{id:"332507",title:"Dr.",name:"Alexey",surname:"Belogurov",slug:"alexey-belogurov",fullName:"Alexey Belogurov"},{id:"332508",title:"Dr.",name:"Irina",surname:"Balmasova",slug:"irina-balmasova",fullName:"Irina Balmasova"}],corrections:null},{id:"74078",title:"Blood-Brain Barrier Dysfunction in the Detrimental Brain Function",doi:"10.5772/intechopen.94572",slug:"blood-brain-barrier-dysfunction-in-the-detrimental-brain-function",totalDownloads:348,totalCrossrefCites:3,totalDimensionsCites:3,hasAltmetrics:0,abstract:"The blood circulation interface and the neural tissue feature unique characteristics encompassed by the term blood -brain barrier (BBB). The barrier’s primary functions are maintenance of brain homeostasis, selective transport, and protection, all of them determined by its specialized multicellular structure. The BBB primarily exists at the level of the brain microvascular endothelium; however, endothelial cells are not intrinsically capable of forming a barrier. Indeed, the development of barrier characteristics in cerebral endothelial cells requires coordinated cell–cell interactions and signaling from glial cells (i.e., astrocytes, microglia), pericytes, neurons, and extracellular matrix. Such an intricate relationship implies the existence of a neurovascular unit (NVU). The NVU concept emphasizes that the dynamic BBB response to stressors requires coordinated interactions between various central nervous system (CNS) cell types and structures. Every cell type makes an indispensable contribution to the BBBs integrity, and any cell’s failure or dysfunction might result in the barrier breakdown, with dramatic consequences, such as neuroinflammation and neurodegeneration. This chapter will focus on the structure and function of the BBB and discuss how BBB breakdown causes detrimental brain function.",signatures:"Alejandro Gonzalez-Candia, Nicole K. Rogers and Rodrigo L. Castillo",downloadPdfUrl:"/chapter/pdf-download/74078",previewPdfUrl:"/chapter/pdf-preview/74078",authors:[{id:"201974",title:"Dr.",name:"Rodrigo L.",surname:"Castillo",slug:"rodrigo-l.-castillo",fullName:"Rodrigo L. Castillo"},{id:"326018",title:"Dr.",name:"Alejandro",surname:"González-Candia",slug:"alejandro-gonzalez-candia",fullName:"Alejandro González-Candia"},{id:"331098",title:"Dr.",name:"Nicole K.",surname:"Rogers",slug:"nicole-k.-rogers",fullName:"Nicole K. Rogers"}],corrections:null},{id:"73588",title:"Physical and Cognitive Therapy (PCT) in Critically Ill Patient",doi:"10.5772/intechopen.94154",slug:"physical-and-cognitive-therapy-pct-in-critically-ill-patient",totalDownloads:264,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"The condition of Critically ill patients in the Intensive Care Unit (ICU) can make heavier impairment physical and cognitive functions. The research objective is to prove that physical-cognitive therapy affects towards increasing physical and cognitive functions to Critically ill patients in ICU. The research design was a Randomized Controlled Trials (RCTs). The samples were Critically ill patients in the ICU of Kediri Baptist Hospital as many as 64 Critically ill patients according to inclusion and exclusion criteria. The research has got ethical clearance from the Committee Ethics Medical Faculty of Diponegoro University. The research instrument used Physical Function ICU Test (PFIT) Indonesian Version and Mini-Mental State Examination (MMSE) Indonesian Version. The differential test used Independent t-test on physical function and Mann-Whitney test on cognitive function towards the intervention group and control group. The results showed that physical-cognitive therapy significantly affected increasing physical function (P < 0.001) with a mean increase of 3.2 points and cognitive function (P < 0.001) with a mean increase of 7.3 points. The difference test of influence between the intervention group and the control group was done by testing the posttest data on physical function (P < 0.001) and cognitive function (P < 0.001) in both groups. Effect size >0.8 (Physical Function: 3.2; Cognitive Function: 1.9). In conclusion, there was affecting physical-cognitive therapy towards increasing physical and cognitive functions to Critically ill patients in ICU.",signatures:"Heru Suwardianto",downloadPdfUrl:"/chapter/pdf-download/73588",previewPdfUrl:"/chapter/pdf-preview/73588",authors:[{id:"324004",title:"Dr.",name:"Aa",surname:"Sdasa",slug:"aa-sdasa",fullName:"Aa Sdasa"}],corrections:null},{id:"74977",title:"Brain Functional Architecture and Human Understanding",doi:"10.5772/intechopen.95594",slug:"brain-functional-architecture-and-human-understanding",totalDownloads:336,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The opening line in Aristotle’s Metaphysics asserts that “humans desire to understand”, establishing understanding as the defining characteristic of the human mind and human species. What is understanding and what role does it play in cognition, what advantages does it confer, what brain mechanisms are involved? The Webster’s Dictionary defines understanding as “apprehending general relations in a multitude of particulars.” A proposal discussed in this chapter defines understanding as a form of active inference in self-adaptive systems seeking to expand their inference domains while minimizing metabolic costs incurred in the expansions. Under the same proposal, understanding is viewed as an advanced adaptive mechanism involving self-directed construction of mental models establishing relations between domain entities. Understanding complements learning and serves to overcome the inertia of learned behavior when conditions are unfamiliar or deviate from those experienced in the past. While learning is common across all animals, understanding is unique to the human species. This chapter will unpack these notions, focusing on different facets of understanding. The proposal formulates hypotheses regarding the underlying neuronal mechanisms, attempting to assess their plausibility and reconcile them with the recent ideas and findings concerning brain functional architecture.",signatures:"Yan M. Yufik",downloadPdfUrl:"/chapter/pdf-download/74977",previewPdfUrl:"/chapter/pdf-preview/74977",authors:[{id:"325644",title:"Dr.",name:"Yan M.",surname:"Yufik",slug:"yan-m.-yufik",fullName:"Yan M. Yufik"}],corrections:null},{id:"73682",title:"The Neurofunctional Model of Consciousness: The Physiological Interconnectivity of Brain Networks",doi:"10.5772/intechopen.94221",slug:"the-neurofunctional-model-of-consciousness-the-physiological-interconnectivity-of-brain-networks",totalDownloads:487,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,abstract:"The present chapter integrates neural networks’ connectivity into a model that explores consciousness and volitional behavior from a neurofunctional perspective. The model poses a theoretical evidenced-based framework that organizes the brain journey of neural information flow from the ascending reticular activating system and non-specific thalamic nuclei, to cortical networks, such as the default mode network and the fronto-parietal network. These inter-connected brain networks can be divided within three hierarchical and inter-connected “functional neural loops”: (1) the “brainstem-thalamic neural loop” for arousal, (2) the “thalamo-cortical neural loop” for neural information distribution throughout the brain, and (3) the “cortico-cortical neural loop” for transforming neural information into the contents of consciousness that the individual can perceive and manipulate voluntarily. These three neural loops act as a global functional neural system, and its disruption due to brain damage can cause a person to experience catastrophic outcomes, such as a coma, a vegetative state, a minimal conscious state, or other cognitive and behavioral impairments.",signatures:"Umberto León-Domínguez",downloadPdfUrl:"/chapter/pdf-download/73682",previewPdfUrl:"/chapter/pdf-preview/73682",authors:[{id:"325488",title:"Dr.",name:"Umberto",surname:"León-Domínguez",slug:"umberto-leon-dominguez",fullName:"Umberto León-Domínguez"}],corrections:null},{id:"74696",title:"Interplay between Primary Cortical Areas and Crossmodal Plasticity",doi:"10.5772/intechopen.95450",slug:"interplay-between-primary-cortical-areas-and-crossmodal-plasticity",totalDownloads:520,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:1,abstract:"Perceptual representations are built through multisensory interactions underpinned by dense anatomical and functional neural networks that interconnect primary and associative cortical areas. There is compelling evidence that primary sensory cortical areas do not work in segregation, but play a role in early processes of multisensory integration. In this chapter, we firstly review previous and recent literature showing how multimodal interactions between primary cortices may contribute to refining perceptual representations. Secondly, we discuss findings providing evidence that, following peripheral damage to a sensory system, multimodal integration may promote sensory substitution in deprived cortical areas and favor compensatory plasticity in the spared sensory cortices.",signatures:"Christian Xerri and Yoh’i Zennou-Azogui",downloadPdfUrl:"/chapter/pdf-download/74696",previewPdfUrl:"/chapter/pdf-preview/74696",authors:[{id:"326935",title:"Ph.D.",name:"Christian",surname:"Xerri",slug:"christian-xerri",fullName:"Christian Xerri"},{id:"336153",title:"Dr.",name:"Yoh'I",surname:"Zennou-Azogui",slug:"yoh'i-zennou-azogui",fullName:"Yoh'I Zennou-Azogui"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"3846",title:"Neurochemistry",subtitle:null,isOpenForSubmission:!1,hash:"671f065e6c1035adb042edc442626b8a",slug:"neurochemistry",bookSignature:"Thomas Heinbockel",coverURL:"https://cdn.intechopen.com/books/images_new/3846.jpg",editedByType:"Edited by",editors:[{id:"70569",title:"Dr.",name:"Thomas",surname:"Heinbockel",slug:"thomas-heinbockel",fullName:"Thomas Heinbockel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1657",title:"Neuroscience",subtitle:null,isOpenForSubmission:!1,hash:"e9a76a5d4740bdeefa66bb4cd6162964",slug:"neuroscience",bookSignature:"Thomas Heinbockel",coverURL:"https://cdn.intechopen.com/books/images_new/1657.jpg",editedByType:"Edited by",editors:[{id:"70569",title:"Dr.",name:"Thomas",surname:"Heinbockel",slug:"thomas-heinbockel",fullName:"Thomas Heinbockel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5521",title:"Synaptic Plasticity",subtitle:null,isOpenForSubmission:!1,hash:"9eea3c7f926cd466ddd14ab777b663d8",slug:"synaptic-plasticity",bookSignature:"Thomas Heinbockel",coverURL:"https://cdn.intechopen.com/books/images_new/5521.jpg",editedByType:"Edited by",editors:[{id:"70569",title:"Dr.",name:"Thomas",surname:"Heinbockel",slug:"thomas-heinbockel",fullName:"Thomas Heinbockel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6089",title:"Sensory Nervous System",subtitle:null,isOpenForSubmission:!1,hash:"87928c04aaa3d4dc4117bd9bb6b599e7",slug:"sensory-nervous-system",bookSignature:"Thomas Heinbockel",coverURL:"https://cdn.intechopen.com/books/images_new/6089.jpg",editedByType:"Edited by",editors:[{id:"70569",title:"Dr.",name:"Thomas",surname:"Heinbockel",slug:"thomas-heinbockel",fullName:"Thomas Heinbockel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7329",title:"Histology",subtitle:null,isOpenForSubmission:!1,hash:"9af2e2fd8f28c4d1b8b9510c3d73e1ec",slug:"histology",bookSignature:"Thomas Heinbockel and Vonnie D.C. 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He was an ENT registrar at the Royal Infirmary, Middlesbrough, United Kingdom in 1993 and subsequently a JW Fulbright scholar at the University of Pittsburgh, USA in 1997. During his Fulbright experience, he also worked at the Hospital of University of Pennsylvania (HUP), Philadelphia and St Joseph’s Hospital, Chicago, USA with sub-specialty interest in rhinology and aesthetic nasal surgery. Dr BS Gendeh retired after 38 years government service as a consultant ENT surgeon at the National University of Malaysia Medical Centre (UKMMC) in 2014, and presently is a Visiting Professor at the Department of Otorhinolaryngology-Head and Neck Surgery at UKMMC and is a resident ENT consultant at Pantai Hospital Kuala Lumpur since 2014. Is an executive member of numerous National and International bodies including Board Chairman of Malaysian American Commission on Educational Exchange (MACEE) from 2013-2015. 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Sweet orange seeds were introduced by the Portuguese jesuits 30 or 40 years after the discovery of Brazil (1500), in the States of Bahia and São Paulo. Due to favorable ecological conditions, the trees (as seedling) produced quite well. The activity remained unknown until the nineteenth century when, during the colonial period, the fruits of the ‘Bahia’ (‘Washington Navel’) orange, originated in the Bahia State, were recognized by the Portugal reign as being larger and juicier than those produced in that country. More important fact, however occurred after its introduction in California it was recognized as ‘more important as the gold extracted from the soils of the Golden State’ and considered as responsible for the development of the citriculture in the five continents. Nevertheless, only in the 1930s, the citriculture began to be implanted commercially in States of São Paulo, Rio de Janeiro and Bahia, with greater growth rate in the states of the Southeast. This chapter is a review on the Brazilian citriculture focusing the four main citrus poles (Figure 1) with their respective producing states and geographical locations, climate, harvested area, production and yield.
Map of Brazil with the physiographic regions and the main citrus poles. (1) South, represented by the State of Rio Grande de Sul (temperate climate), (2) São Paulo, Minas Gerais and Paraná States (central part of the country), (3) Amazon basin, represented by the States of Amazonas and Pará (equator region) and (4) Northeast, represented by the States of Bahia and Sergipe (typical tropical region).
There are no climatic limitations for citrus growing in Brazil. Irrigation is not necessary, except in the semiarid areas of the Northeast, where the rainfall is below 700 mm and in the south where frosts can occur. The altitude varies from 20 to 500 m. Rainfall varies from 1,000 to 1,800 mm, during the winter in the Northeast (March–August) and in the summer in the Southeast (September–March). In Rio Grande do Sul, the rainfall is almost monthly. The relative humidity is higher in the Northeast, where in the winter it almost reaches 100%, with the annual average being between 75 and 80%. The annual average temperature varies from 19°C in the South to 25°C in the Northeast. Independent of the area, flowering occurs in September, one or more times depending on the distance to equator. The farther from the equator, smaller are the fruits but they stay on the trees longer. The soils of the citrus-growing areas are sandy/loam, deep, well drained, but with poor fertility especially in phosphorous. Except the shallow soils of some areas, like the cocoa-growing area in Bahia, the humid Amazonian area or the loamy areas of the States of Paraná and São Paulo, where the coffee and the sugarcane are cultivated, there is an immense area which is available to the citrus industry in Brazil. In an analysis on the Brazilian territory (8.5 millions square meters), it would be possible to adopt a classification of the citriculture on four main citrus poles which are described as follows.
The citrus production in the South of the country is represented by the State of Rio Grande do Sul, which is achieved in 2016, 553,372 tonnes, being the largest concentrations of sweet orange (71.5%) and mandarin (25.4%) [8].
There are 35 microregions in the State of Rio Grande do Sul, 34 of them produce citrus (Figure 2). The regions that most stand out are: Montenegro, Frederico Westphalen and Erechim. The microregion of Montenegro has its production concentrated in orange (45.8%) and mandarin (47.0%) and only 7.2% in lemon. The most important counties are Montenegro, Harmonia, Pareci Novo, Tupandi and São José do Hortêncio. From these, Montenegro highlights the production of mandarin. The second most important microregion is Frederico Westphalen, whose participation in the production was 91.9% of orange, 7.1% of mandarin and 1.0% of lemon. From the 27 remaining countries that compound the microregion, only 3 deserve special mention: Liberato Salzano, Planalto and Alpestre. The microregion Erechim comes next and it is composed of 30 counties, the most important ones being Aratiba, Itatiba do Sul and Mariano Moro.
Concentration of the citrus production in Rio Grande do Sul in the principal microregions. Source: [
In the State of Rio Grande do Sul, the latitudes varies from 27°14′56″ S in Alpestre to 30°53′27″ S in Santana do Livramento do Sul near to Uruguay. Longitudes varies from 53°02′06″ to 55°31′58″ W in the same municipalities. Annual media temperature varies from 19.8 to 18.4°C and the rainfall from 1,892 to 1,467 mm in the same municipalities. The climate of the State of Rio Grande do Sul is humid subtropical (or temperate). It is constituted by four reasonably well-defined seasons, with moderately cold winters and hot summers (mild in the higher parts), which are separated by intermediate seasons of approximately 3 months of duration and rains well distributed along the year. Due to its latitudinal situation (inserted in the context of the average latitude), Rio Grande do Sul presents peculiar features different from the climate of the rest of Brazil. The temperatures of the state, in diverse regions, are among the lowest ones of the Brazilian winters, reaching 6°C in cities like Bom Jesus, São José dos Ausentes and Vacaria, where frequent frosts and occasional snowfall happen, and where it is not recommended in the planting of citrus. There are still the altimetric differences, with special feature for Serra do Sudeste and Serra do Nordeste, which is not recommended for planting of citrus because of the high frequency of frosts. During autumn and winter, the state is also liable to the summer phenomenon, which consists of a succession of days with not normal high temperatures for the season. Different from the other states of Brazil, the occurrence of heavy frosts is relatively strong in the whole state demanding the usage of rootstock tolerant to cold.
The citriculture of the State of Rio Grande do Sul comprehends an almost complete chain, involving around 20,000 farmers, more than 100 nurserymen, producers of various inputs, beneficiators of fruit, industries of concentrated and ready to drink juices and of others byproducts of the fruit, wholesalers, marketers, retailers and around 11 millions of consumers. The annual production of orange is 396,000 tonnes (24,000 ha), of mandarin is 141,000 tonnes (11,000 ha) and of acid limes and true lemons is 17,000 tonnes (1,400 ha), being the state, respectively, the sixth, the fourth and the sixth greatest national producer of these fruits [8]. Even so, Rio Grande do Sul imports from others states, especially from Paraná and São Paulo, and from others countries, principally from Spain and Uruguay, almost 50% of the citrus which consume fruit and juice. The vast majority of the citrus growers is family-based, being the average planted area with citrus beneath two hectares per property. The business citriculture is conducted by less than a hundred producers located mainly in the regions of Vale do Caí and Campanha Gaúcha, with the cultivated area of 3–300 ha per property. The associativism is very practiced in Rio Grande do Sul, notably in Vale do Caí, wherewith the small citrus growers seek to overcome their limitations of production, mostly in the processing and in the marketing of the fruit. The principal poles of production are found in Vale do Caí, Campanha Gaúcha and in the northwest region of the state. The citriculture of the Vale do Caí exists for three generations, standing out, nowadays, for the production of mandarins. In the northwest region, the citriculture is much more recent and its expansion was supported by Emater – RS, it concerns small orchards where the orange tree Valência is primarily cultivated and good part of the fruits is destined to the industrial process. In the Campanha Gaúcha region, the production pole of seedless citrus is found. It was initiated in 1998 with the support of Embrapa Clima Temperado, where it is cultivated approximately 2500 hectares and the production is marketed in the principal supermarket network of the state and in others parts of the country. For cultivars, the region of the Vale do Caí detaches in the production of Montenegrina (principal), Caí and Pareci mandarins; the northwest region in orange tree Valência (principal) and Folha Murcha; and the Campanha Gaúcha in navel orange tree Navelina, Lane Late and Cara Cara (Figure 3), orange tree Salustiana, mandarin tree Okitsu and hybrids Ortanique and Nadorcott (Figure 4) and other varieties (Figure 5). The Trifoliata is the principal rootstock used, highlighting itself by the longevity of the plants, the tolerance to various diseases and to induce the high quality of the fruits. The system of conventional production is used in the great majority of citric properties. However, there are more than one hundred of organics products and practically the same number using the principles of integrated production. Among the main limitations of the culture, the phytosanitary nature ones are bounced. According to the producers, the black spot disease is outstandingly the biggest problem of the region of the Vale do Caí, followed by the citrus canker and by the brown spot of alternate. These two last diseases have been controlled especially by the usage of tolerant cultivars. The black pint and the brown spot of alternate do not exist up to the moment in the region of the Campanha Gaúcha, where the citric canker is the major limiting factor. These disease is endemic in the larger part of Rio Grande do Sul and it causes great losses notably in the rainy season. The handling of the disease has been conducted by means of spraying copper-based products and specific cultural practices to reduce source of inoculum. The Huanglongbing (HLB) has not been found in Rio Grande do Sul yet, according to the annual lifting accomplished by the Ministério da Agricultura, Pecuária e Abastecimento (MAPA) in partnership the Embrapa Clima Temperado. However, the vector insect exists in some regions. Although there are around 10 juice and citrus byproducts industries, the production is directed mainly to the market of fresh fruits, prioritizing the state demand.
‘Cara Cara’ (navel) sweet orange in Rio Grande do Sul, the first producing Brazilian state for fresh consumption. Source: Roberto Pedroso.
Harvesting of ‘Nadorcott’ mandarin in Rio Grande do Sul. Source: Roberto Pedroso.
‘Nova’ tangelo and ‘Meyer’ lemon in Rio Grande do Sul. Source: Roberto Pedroso.
The production of citrus in the principal citrus pole of the country encompasses the States of Minas Gerais, São Paulo and Paraná. The production from São Paulo, the most expressive one, is distributed in sweet orange, lemon and mandarin, with volumes of 12.8 million, 875,000 and 345,000 tonnes in 2016, respectively, in order of importance. In the State of Minas Gerais, the citrus production achieved 1,258,767 tonnes being 80% of orange and 13% of mandarin and 7% of lemon. The State of Paraná produced 922,422 tonnes of citrus—80% of orange and 20% of mandarin [8]. There are 63 microregions in the State of São Paulo, and from these, 25 microregions are the most important in the citrus production (Figure 6). Of these 25, the highest concentrations are in 7 microregions, in order of importance: Bauru, Avaré, São João da Boa Vista, Araraquara, São José do Rio Preto, Jaboticabal and Itapetininga. Lower concentrations occur in 18 microregions: Barretos, Botucatu, Mogi Mirim, Pirassununga, Itapeva, Novo Horizonte, Jales, Ourinhos, Catanduva, Limeira, Rio Claro, São Carlos, Franca, Lins, Fernandópolis, Jaú, Piracicaba and Sorocaba. Although Minas Gerais owns 66 microregions, just 2 of them stand out in the production of citrus: Frutal and Uberlândia. Both of them are part of the Triângulo Mineiro and in 2016 they produced about 414,000 and 259,000 tonnes, respectively. In the microregion of Frutal, the most important counties are Comendador Gomes and Frutal, while in the microregion of Uberlândia the counties that most highlight are Prata, Uberlândia and Monte Alegre de Minas. There are 39 microregions in Paraná, of which only 2 do not produce citrus. The two most important microregions in the citrus production are Paranavaí and Cerro Azul. Both microregions produce citrus, but Paranavaí presents the greatest volume in the orange production (99.4%) and Cerro Azul calls attention in the mandarin production (92.4%). The microregion of Paranavaí owns 29 counties, of which 9 do not produce any kind of citrus and the 3 that more stand out are Paranavaí, Guairaçá and Alto Paraná. In the microregion of Cerro Azul, two counties highlight, Cerro Azul and Doutor Ulysses, both of them concentrate their productions to the mandarin fruit.
Concentration of the citrus production in the states of Minas Gerais, São Paulo and Paraná, concerning the principal microregions. Source: [
Citrus trees are cultivated in São Paulo State often under mountain subtropical climate, that is, Cwa according to Köppen’s classification. Considerable areas are in Cfa climate, and minor cultivation is carried under Aw and Cfb climates, respectively, on the coast and in the highlands. Considering Cwa as the prevalent condition, climate is characterized with hot, rainy summers, and dry, relatively cold winters. Two main climate types for citrus cultivation could be described: (i) mean annual air temperature higher than 17°C and annual water deficit of 0–60 mm and (ii) mean annual air temperature higher than 17°C and annual water deficit higher than 60 mm [16]. Minimal air temperatures are in the range of 8–10°C, and maximum can surpass 40°C. Annual rainfall ranges from 1,000 to 2,000 mm, often 1,400–1,800 mm, with distribution concentrated from November to March. Altitude ranges from 400 to 1000 m, but 550–750 m is prevalent. Citrus areas are free of severe frosts in São Paulo, even though it is regularly observed in the South of the State and in Paraná. Prolonged drought is frequent, especially on the North of São Paulo and in Minas Gerais State, as drought intensity decreases with the latitude. In recent years, heat stress associated to drought was reported in the main citrus areas in September–October, which is the period of the main blossom and fruit set.
The citrus belt comprises the Northwest of Paraná State (23°04’ S–52°27’ S); the Triângulo de Minas Gerais region (19°18’ S–48°55’ S) and São Paulo State (21°49’ S–49°12’ S), which is divided in the following areas (as percentage of the total citrus area in this state): North (22%), Northwest (11%), Center (29%), South (20%) and Southwest (18%) [16].
São Paulo, Minas Gerais and Paraná had about 430,000, 38,000 and 25,000 ha of sweet orange groves in 2016–2018, respectively [5, 6]. The main varieties are, in decreasing order, Pera (midseason), Valencia (late), Hamlin (early), Natal and Folha Murcha (both late) and the early season varieties of Valencia Americana, Westin and Rubi, although the former four comprise more than 80% of the total trees. Some other varieties including navels and acidless oranges are cultivated in smaller areas. Persian lime and lemons are also cultivated mainly in São Paulo (39,000 ha in 2018), and mandarins, largely Ponkan mandarin and Murcott tangor, are important for all states (12,000; 8,000 and 10,000 ha for São Paulo, Minas Gerais and Paraná, respectively). Sweet oranges are produced mainly for juice processing, and the citrus belt represents more than 85% of the Brazilian production. This is the most important orange production area in the world (34%) resulting in 56% of the juice produced and 76% of the marketed in the world [11]. Almost 97% of the juice is exported, while mandarins are for fresh fruit in the internal market, and limes and lemons are for fresh fruit and few processing, and exportation of fresh fruit too. Rangpur lime was the most used rootstock until the 2000s, as a result of its tolerance to both citrus tristeza virus (CTV) and drought, high and early yield, and great vigor and graft compatibility in the nursery. However, it is sensitive to citrus sudden death (CSD), blight, citrus nematode and gummosis of
The citrus industry in São Paulo, Minas Gerais (Figure 7) and Paraná (Figure 8) employs more than 200,000 people and contributes with US$ 6.5 billion annually. Although about 6,000 farms cultivate oranges, 88% of the growers have less than 50,000 trees, while 12% of farms with more than 100,000 trees correspond to 77% of the total trees (194 millions) [6]. Therefore, the citrus cultivation in the citrus belt is nowadays a highly intensive, technological entrepreneurial activity. However, harvesting and fruit transportation reaches almost 50 of the production cost (Figure 9). Nursery stocks have been grown in insect-proof screen houses since 2003, and about 10 million grafted trees are produced annually in pots filled with potting media. Orchards use currently an average of 484 trees/ha, but new groves increased tree density to 656 trees/ha in average. About a third of the area is currently irrigated, and major cultivated area corresponds to trees from 5 to 15 years old. Citrus diseases and pests are major limiting factors to the citrus industry of the three states that substantially increase the production costs. Huanglongbing (HLB) is the most devastating one, and the average incidence in São Paulo and Triângulo de Minas Gerais was about 17% in 2017 [7]. The smaller the farm, the higher the incidence, because HLB management essentially depends on the eradication of symptomatic trees and on the control of the vector, the Asian citrus psyllid, in addition to control measures on inoculum sources outside the farm. As a result, management is more efficient if taken by all growers in an area wide approach. Other important phytossanitary problems include black spot, citrus canker, leprosis virus, citrus variegated chlorosis, citrus sudden death, post bloom fruit drop (
Ponkan mandarin orchard in Minas Gerais. Source: Eduardo Girardi.
Planting of citrus in Paraná. Source: Eduardo Girardi.
Harvesting of sweet orange in São Paulo, the first citrus-producing state in Brazil. Source: Eduardo Girardi.
Considering the enormous area of Northern Brazil, citriculture is poorly exploited in this region, with the States of Pará and Amazonas showing the highest productions. From 270,370 tonnes of sweet orange, 53,806 tonnes of acid lime and 4,722 tonnes of mandarin, the State of Pará is responsible for 70.8% of sweet orange, 73.9% of acid lime and 20.9% of mandarin, while in the State of Amazonas these values are 14.9, 4.2 and 6.7%, respectively. Cultivated area comprises only 19,515 ha with the following distribution: 15,876 ha of sweet oranges, 3,054 ha of lemons/limes and 585 ha of mandarins. Average yield in these states is 14.1 t/ha indicating that the regional yield is about 54.6% of the national average (25.8 tonnes/ha).
All states in the North of Brazil produce citrus. However, Pará and Amazonas are highlighted once contribute with 70.6 and 13.0%, respectively, of the regional production, and these states rank in seventh and thirteenth position among Brazilian citrus-producing states. There are 22 microregions in the State of Pará, but citrus is cultivated in 17 of them. In this state, the two main citrus-producing areas are Guamá and Santarém. The former has the major concentration of citrus crops (sweet orange, lime/lemon and mandarin) (Figure 10). In the Guamá area, the greatest producer is the municipality of Capitão Poço, most notably with oranges, while in the Santarém area the production of lemon/lime is more important in the municipalities of Monte Alegre and Alenquer. The State of Amazonas has 13 microregions, and citrus production is mainly sweet orange cultivated in the Rio Preto da Eva microregion in the municipality with the same name.
Concentration of the citrus production in the States of Amazonas and Pará, concerning the principal microregion. Source: [
The North region consists of the largest part of the Amazon Basin and it is characterized by low altitudes between 0 and 200 m. The climate is tropical equatorial with predominance of the type Af in the States of Amazonas and Acre, and of the type Am in the States of Pará, Amapá, Roraima and Rondônia. Only the State of Tocantins presents the climate type Aw. Atmospheric circulation systems, in the intertropical convergence zone, are responsible for the climate variability and for the rains in the state of the Amazon Basin. The average annual precipitation exceeds 2,000 mm, as until 3,000 mm in the estuary of the Amazonas River in Belém, and 2,400 mm in the innermost region of the Amazon Basin, in Manaus. In the direction of Roraima, East of Pará, there is less rainfall, with the annual total in the order from 1,500 to 1,700 mm. The rainy season in the greatest part of the region comprehends the period from December to May. During the rainiest months, March and April, precipitations of up to 400 mm monthly are reached. The ‘dry season’ from June to November still shows precipitations of 60–120 mm per month. Unlike, in the State of Roraima, due to the influence of the climatic conditions from the North hemisphere, the maximum rainfall indices occur in the period from April to September, with a longer dry season between October and March. Concerning the temperatures, the predominant climate is hot, with average annual temperatures varying from 22 to 28°C, average temperature of the coldest month of 18°C and maximum of 42°C in the hottest months. The temperatures are high in most of the region with low thermal amplitude except in some locals of higher altitude in Roraima and in Acre. In Rondônia, due to the entrance of cold air masses from the Atlantic Ocean, passing by the State of Mato Grosso, temperatures are reduced causing the phenomenon of ‘coldness’ for short periods of 5–6 days.
Considered as the largest citrus pole in the equatorial zone (Amazon basin), the citriculture of Pará is represented by the municipality of Capitão Poço in an area of 11,000 of hectares [4]. The fruit production, made by at least 1,000 growers, is destined for other states including for juice processing plants. It is reference as organic orange producer, being 70% of family farming, and the municipality restarted its certification process [9]. Different as compared to other producers in Brazil, the harvesting season occurs from September to December with a minor harvest in March and April. As in the Northeast region, the combination scion/rootstock cultivated is ‘Pera’ sweet orange × ‘Rangpur’ lime and the yield of orange and acid lime is very low, around 15 tonnes per hectare per year.
Big ‘Pera’ sweet orange tree in Amazonas. Source: Luciano Souza.
‘Pera’ sweet orange fruits in Amazonas. Source: Luciano Souza.
Sweet orange, lime and mandarin fruits are being produced in the states of the Northeast region, however the States of Alagoas, Pernambuco and Piauí do not produce mandarin. From the nine Northeastern States, Bahia and Sergipe stand out, with 66.2 and 26.1% of the regional production, and second place in the national production. From 1,744,673 tonnes of sweet orange, 169,123 tonnes of acid lime and 34,247 tonnes of mandarin, the State of Bahia is responsible for 64.8% of sweet orange, 88.1% of acid lime and 30.0% of mandarin, while in the State of Sergipe these values are 28.0, 4.9 and 30.3%, respectively. In these states, the citriculture occupies an area of 127,517 ha as follows: sweet orange 118,473 ha, acid lime 7,769 ha and just 1,275 ha with mandarin. The yield average is very low, just 14 tonnes/ha, representing almost half of the national average.
The Northeast region is located between 2 and 18° South latitude and 35° and 50° West longitude. The climate along the sea coast is hot and humid (tropical), with annual temperature average varying between 20 and 28°C and rainfall between 300 and 2,000 mm. The sunshine time varies from 2,300 per year in the humid areas up to 3,000 in the semiarid areas. The largest area in the Northeast is under semiarid conditions (‘Polígono das Secas’)—less than 750 mm of rain per year), The region comprises nine states: Maranhão, Piauí, Ceará, Rio Grande do Norte, Paraíba, Pernambuco, Alagoas, Sergipe and Bahia, that occupies 18.2% of the national territory. Analyzing the regions and its ecological diversity, in relation to the citrus trees, it is possible divide them in three grand zones: (1) sea coast (Coastal Tablelands) represented by the municipality of Cruz das Almas (BA); (2) area of altitude, represented by the municipality of Morro do Chapéu—Chapada Diamantina (BA), over 1,000 m of altitude and (3) semiarid zone, represented by the municipality of Petrolina (PE).
The sea coast (Coastal Tablelands) is located along the sea, near the main capitals. The relative humidity is high and rainfalls around 1,000 mm per year but very concentrated during the summer time (December–March). Under these conditions, it predominates the sweet orange group represented almost exclusively by ‘Pera’ sweet orange (Figure 13), which fruit quality is typical in the tropical areas: larger fruits, juicier, less colored and less acid than those produced under subtropical conditions. More recently, the ‘monocitriculture’ of ‘Pera’ sweet orange × ‘Rangpur’ lime rootstock (almost 100% of the orchards) has been broken by the use of ‘Tahiti’ acid lime, unfortunately on the same rootstock. The fruit production destination is divided between the fresh fruit market and for processing (frozen concentrated juice). For a long time, Embrapa is stimulating the scion and rootstock diversification recommending as early varieties: ‘Rubi’, ‘Westin’ and ‘Salustiana’; midseason: ‘Pineapple’, ‘Pera’ and ‘Sincorá’; late: ‘Natal’, ‘Valencia’ and ‘Folha Murcha’ (Curled Leaf) [1], as well the following rootstocks: ‘Indio’, ‘Riverside’ and ‘San Diego’ citrandarins (from USDA), ‘Sunki Tropical’ mandarin and ‘Santa Cruz Rangpur’ lime. News rootstock hybrids are being released by the Embrapa Citrus Genetic Improvement Program [15] due to traditional areas that represent the Northeastern citriculture, the analyses on fruit productions will be concentrated in the States of Bahia and Sergipe. In Bahia, there are 32 microregions but only 4 can be considered as citrus producer: Alagoinhas, Santo Antonio de Jesus, Ribeira do Pombal and Entre Rios (Figure 14). From these, the first presents the largest citrus concentration represented by the municipalities of Rio Real, Inhambupe and Alagoinhas. In the Santo Antonio de Jesus microregion, sweet orange, acid and sweet lime and mandarin fruits are produced in the municipalities of Cruz das Almas, Sapeaçu, Muritiba, Governador Mangabeira and Cabaceiras do Paraguaçu as the most important. In Cruz das Almas, the largest participation comes from acid lime designated to the exporting market. Ribeira do Pombal microregion is concentrated just on sweet orange production and is located in a climatic transition zone which rainfall is less than 1,000 mm. The most important municipality is Itapicuru and its neighbors where exist the most appropriate conditions in the State for the citrus expansion, due to the existence of Tucano aquifer. In Entre Rios microregion, sweet orange production is concentrated in the municipalities of Esplanada and Jandaíra. In Sergipe State, there are 13 microregions being the most important, in a descending order, Boquim, Estância and Agreste de Lagarto. The Boquim microregion is most important in the production of sweet orange, mandarin and limes mainly in the municipalities of Itabaianinha, Cristinápolis, Salgado, Boquim, Arauá, Umbaúba and Tomar do Geru. In the microregion Estância, similarly, the citrus production is concentrated in the same groups. The main municipality producers are Santa Luzia do Itanhy, Estância and Indiaroba. Finally, Agreste de Lagarto microregion is predominated with the sweet orange and mandarin, mainly in the municipalities of Lagarto and Riachão do Dantas.
‘Pera CNPMF D-6’ sweet orange in Bahia—The most popular variety in Brazil. Source: Orlando Passos.
Concentration of the citrus production in the states of Bahia and Sergipe, considering their microregions. Source: [
It is located in the States of Bahia, Pernambuco, Paraíba and Ceará with milder climate, low temperatures in the winter (July is the coldest month), and insufficient rainfall for the culture necessity, what requires complementary irrigation. Inside this ecosystem is the Chapada Diamantina tableland, whose altitude varies between 1,000 and 1,400 m. In this zone, the table fruits should be prioritized, preferably the mandarins without despising the seedless navel oranges (‘Bahia’ sweet orange). Among these fruits, some stand out: ‘Cara Cara’ (‘Bahia’ of red pulp), ‘Baianinha’ (litle Navel) and ‘Lima’ (no acidity). In the mandarins group, beyond the traditional ‘Ponkan’ and ‘Murcott’, special attention should be given to the tangelo mandarin tree ‘Page’ (seedless fruit, in isolated plantation), to the tangor mandarin tree ‘Piemonte’ (Figure 15) and to the BRS Salibe Murcott (fruits with few seeds).
‘Piemonte’ mandarin-tangor in Bahia—A new variety for fresh consumption. Source: Orlando Passos.
The Brazilian semiarid is an ecoregion defined from the isoieta of 800 mm. The climate can be classified, according to Köepen, as type Bswh, which corresponds to a very hot semiarid region. The annual rainfall index is 571.5 mm with concentration from December to March [2]. The average annual temperature is 26.4°C, with average minimum of 20.6°C, and with average maximums of 31.7°C. The daily thermal amplitude is around 10°C, monthly of 5–10°C and annually from 1 to 5°C; very strong insolation (annual average of 2,800 h/year); low relative humidity (annual average around 50% per year); and high evapotranspiration (average of 2,000 mm/year) [10, 14]. In areas of hot or tropical climate, like in the Northeast region, the amplitude is smaller, what implies in the fruit production of less coloring, not just inside but also outside. However, the contents of soluble solids (°Brix) are higher and present low acidity, resulting in sweeter fruits, but with the relation Brix/acidity unfavorable. It is worth pointing out that in hotter climates, like in the Northeastern semiarid, grapefruits and ‘Tahiti’ acid lime present a thin peel and a very colorful pulp, besides a great productivity, when compared to fruits produced in others regions of the country. It is important to accentuate that in citrus cultivation under high temperatures, the period between flowering and maturation is reduced, what enables anticipation of the harvesting in relation to the others producing areas. Although having a potential for grapefruit, lemons and acid limes, there are small areas producing citrus in the São Francisco Valley, specifically with ‘Tahiti’ acid lime (Figure 16) [12]. In 2016, the results were 204 ha of planted area with the yield of 26.2 t/ha, in the following counties: Juazeiro, Casa Nova, Sobradinho and Curaçá [8]. In this region, due to its production characteristics, it is recommended rootstocks that determine reduced size to the canopy, drought tolerance and fruits of good quality, like rootstocks hybrids obtained by Embrapa Citrus Breeding Program in crosses with ‘Trifoliate’ orange, ‘Swingle’ citrumelo and ‘Troyer’ and ‘Argentina’ citranges, among others. The citrandarins ‘Indio’, ‘Riverside’ and ‘San Diego’, obtained by USDA Citrus Breeding Program and recommended by Embrapa Mandioca e Fruticultura, are hybrids of ‘Sunki’ mandarin with trifoliate orange, and have been highlighting in the Northeastern citrus scenario, because of their citrus foot-rot tolerance and production of good quality fruits. In researches with citrus fulfilled by Embrapa Mandioca e Fruticultura in partnership with Embrapa Semiárido, in Petrolina-PE and in Juazeiro-BA, it was verified that the grapefruit and the ‘Tahiti’ acid lime behave well. The Flame grapefruit (Figure 17) present thin peel and deep flesh color and fair balance between Brix/acidity, what are considered outstanding characteristics [12]. Some sweet orange varieties have great potential under semiarid conditions, as the clones C-21, D-9, D-12 and D-25 of Pera, and Rubi, Westin, Salustiana, Natal CNPMF-112 and Valencia Tuxpan, besides ‘Page’ and ‘Piemonte’ mandarin hybrids [3]. Examining the different climatic situations, it is possible to point out as competitive advantages of the Northeast region: (1) multiplicity of climates and soils and area availability; (2) geographic privileged localization in relation to the main markets (Economic European Community and United States of America) in comparison to the others citrus fruit producers regions in the country; (3) non-occurrence of bacterial diseases, like the HLB (huanglongbing, ex-greening) and the citrus canker and others like leprosis (not in endemic form) and the black spot, which are causing serious losses to the Brazilian southwest citriculture, mainly in the States of São Paulo, Minas Gerais and Paraná.
‘Tahiti’ acid lime in Bahia—In Ascension in the northeastern region. Source: Nilton Sanches.
‘Flame’ grapefruit in the São Francisco Valley—An option for the regional citriculture. Source: Orlando Passos.
Recently, there has been renewed interest in the use of cannabis in patients with treatment resistant epilepsy. This has, in large part, been driven by a public perception that cannabis offers a safe and natural alternative to conventional anticonvulsant therapies. However, the phytocannabinoids found in the cannabis plant do offer some very unique anticonvulsant pharmacological properties that warrant further exploration.
\nIn this chapter the authors will provide a brief review of epilepsy and epileptogenesis followed by a review of how the endocannabinoid system can alter the processes involved in the propagation and suppression of epileptic seizures. This is then followed by a review of the phytocannabinoids and their anticonvulsant mechanisms of action. Finally, the authors provide a historical background on the use of cannabis to treat patients with epilepsy and a review of the most recent clinical trials.
\nEpilepsy is a chronic disease characterized by recurrent unprovoked seizures. It is defined as a disease of the brain in which the patient has either (1) two or more unprovoked seizures occurring more than 24 hours apart or (2) one unprovoked seizure and a probability of further seizures to be greater than 60% [1]. The prevalence of epilepsy worldwide is estimated to be between 4 and 10/1000 people with epilepsy accounting for up to 0.5% of the global burden of disease [2, 3]. There is significant geographic variation with prevalence rates of epilepsy prevalence rates being much higher in the developing world [4].
\nMost children and adults with epilepsy respond well to anticonvulsant therapy with approximately 50% of adults and 70% of children becoming seizure free with their first anticonvulsant medication [5, 6, 7]. Up to 30% of patients with epilepsy can be considered to be drug resistant which is defined by the International League Against Epilepsy as having failed two or more appropriate anticonvulsant treatments at an appropriate dosage [8, 9].
\nIn patients who have failed two appropriate anticonvulsants the likelihood of seizure freedom with the addition of further anticonvulsant therapies is low. Treatment options for patients with drug resistant epilepsy include further trials of anticonvulsants, resective surgery, neural pathway stimulation with receptive or vagal nerve stimulation and dietary therapies [10]. Further trials of anticonvulsants in adults will result in 16% of patients who had failed their first two medications becoming seizure free [11]. In pediatric patients while the likelihood of achieving remission for 1 year or more with further medication trials is higher at 57%, many will continue to have relapses over time [12]. Resective surgery success rates (as defined as obtaining Engel Class 1 seizure freedom) in pediatric and adult patients with surgically amenable epileptogenic lesions range from 34 to 90% depending on the nature and extent of the lesion [10, 13].
\nA full review of the processes that result in brain abnormalities causing seizures (epileptogenesis) is beyond the scope of this chapter. However, in order to understand how cannabinoids can have potential in treating epilepsy it is worth knowing the basic principles of these processes. One of the major hallmarks of epilepsy is the presence of abnormal oscillatory events within neuronal networks in the form of recurrent interictal spikes and high frequency oscillations within the epileptic zones of the patients’ brain [14]. These abnormal oscillations then result in excessive synchronous firing of neurons causing an epileptic seizure with alteration in the patient’s behavior, motor activity or sensorium. Epilepsy can result from injury (either ischemic or traumatic) to cortical brain structures or genetic, inflammatory, structural and metabolic disturbances within the brain. The main components of the development of the abnormal oscillations within neuronal networks and epileptogenesis (seizure development) are (a) neuronal hyperexcitability—the ability of neurons to generate abnormal intrinsic burst discharges (b) a loss of GABA mediated interneuron neuronal inhibition that would normally prevent these discharges from spreading to adjacent neurons and (c) neuronal hypersynchrony in which excessive synaptic enhancement of neighboring neurons through the development of excitatory pathways allows these bursts to spread in a synchronous manner within a group of neurons [15]. Neuronal hyperexcitability can arise from abnormalities in excitatory or inhibitory neurotransmitter receptors resulting in a loss of the normal balance between neuronal excitation and inhibition. Of particular interest in epileptogenesis are the excitatory glutamatergic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors [16]. Alterations in ion channel function as is seen in the channelopathy associated epilepsies such as Dravet syndrome also lead to neuronal hyperexcitability [17].
\nThe endocannabinoid system comprises the two endogenous endocannabinoid receptors (CB1R and CB2R) their two endogenously produced endocannabinoids; anandamide (
Although CB1R is one of the most abundantly expressed GPCRs in the brain, its expression is concentrated within certain groups of neurons. For example, in the hippocampus, CB1R expression is concentrated on the axon terminals of inhibitory GABAergic CA1 region interneurons and Schaffer collaterals arising from CA3 pyramidal cells [22]. These interneurons play a key role in the formation and maintenance of normal oscillatory behavior in the hippocampus essential for memory formation [18]. The effect of stimulation of CB1R is very localized within neuronal networks both from a spatial and temporal point of view. This is achieved by the production of monoacylglycerol lipase (MAGL) by astrocytes and nerve terminals which breaks down 2-AG in the synaptic cleft. This temporal and spatial control allows for precise regulation of oscillations within neuronal networks by the endocannabinoid system [18].
\nDuring an epileptic seizure there is excessive glutamate release from presynaptic excitatory neurons. In rodent models of epilepsy this has been shown to cause increased production of both 2-AG and anandamide that in turn active CB1R on the glutamatergic axon terminals to decrease the release of further excessive glutamate. This prevents further neuronal hyperexcitability which may play a role in terminating seizures. The increased anandamide is felt to play a role in preventing seizure induced excitatory neurotoxic effects [18, 21].
\nTemporal lobe epilepsy secondary to mesial temporal sclerosis (scarring of the hippocampi) is a common cause of epilepsy in adults that is often amenable to surgical resection of the mesial temporal structures. Pathological examination of surgically resected specimens has shown alterations in expression of CB1R of neurons within the hippocampi that provide insight into how disruption of the endocannabinoid system could predispose to epileptogenesis. In resected hippocampi there is a downregulation of CB1R expression on the axon terminals of excitatory (glutamatergic) neurons within the inner molecular layer of the dentate gyrus and an upregulation of CB1R expression on inhibitory (GABAergic) axon terminals within the dentate molecular layer [18]. These changes in CB1R expression result in both a loss of the normal inhibition of excessive glutamate release and increased suppression of GABAergic activity both of which result in increased neuronal hyperexcitability and subsequent seizure generation [22]. In patients with chronic epilepsy, there is also a decrease in the amount of anandamide and 2-AG released with excessive neuronal activation further contributing to a loss of the endocannabinoid mediated inhibition of excessive neuronal activation [18].
\nThe growing body of evidence demonstrating the role the endocannabinoid system plays in the brains’ mechanisms in regulating neuronal network oscillations and preventing excessive neuronal hyperexcitability coupled with alterations in the endocannabinoid receptors seen in epileptogenic tissue make the endocannabinoid system an attractive therapeutic target in the treatment of epilepsy. Modulation of the endocannabinoid system would provide a potential novel anticonvulsant mechanism not provided by other anticonvulsant therapies.
\nThe phytocannabinoids are a class of cannabinoids that are produced by plants of the cannabis species. The phytocannabinoids are C21 aromatic compounds consisting of an aromatic isoprenyl terpenophenolic core and resorcinyl side chain. Based on the structure of the oxygen bond between the isoprenyl and resorcinyl moieties the phytocannabinoids can be placed into 6 main families. Within each family, variations of the R-chain on the resorcinyl moiety differentiate each individual cannabinoid [23]. To date, over 140 different phytocannabinoids have been identified in
Initial research focused on the anticonvulsant effects of Δ9-THC and other CB1R agonists such as anandamide. Through their activation of CB1R, anandamide and the synthetic cannabinoid WIN 55,212-2 were able to block the production of postsynaptic neuronal spiking and excitatory post synaptic potential production. Both compounds were also able to suppress the production of abnormal burst activity in neurons placed in Mg2+ depleted solution. Depletion of Mg2+ in solution allows activation of NMDA receptors at normal resting potentials without the usual prerequisite neuronal depolarization. This effect was abolished when CB1R antagonists were added, suggesting that the effect was secondary to activation of CB1R by these agents [26]. Δ9-THC is a major phytocannabinoid in
In a rat model of electrically induced limbic seizures Δ9-THC increased the threshold of electrically induced after discharges at the site of electrode implantation in the left subiculum. However, Δ9-THC increased the duration of cortically recorded after discharges in electrodes remote from the site of stimulation. This suggested that Δ9-THC may have both anticonvulsant and proconvulsant effects in focal onset epilepsies [27]. In the cobalt model of focal epilepsy in rats Δ9-THC increased the frequency of epileptic potentials at the site of the cobalt-induced lesion. This was not seen with Δ9-THC’s main metabolite 11-OH-Δ9-THC. Both Δ9-THC and 11-OH-Δ9-THC seemed to increase generalized cortical excitation as seen by the production of brief intermittent cortically recorded after discharges [27]. Similar findings were seen in a rat model using iron to induce a seizure focus. While both Δ9-THC and 11-OH-Δ9-THC both caused increased cortical excitability, only Δ9-THC provoked clinical seizures. As well, the dose of Δ9-THC required to induce seizures was much higher than that required to induce electrographic changes in keeping with cortical excitation [29]. In mice, Δ9-THC has also been shown to induce kindling of a second epileptic focus in response to both electroconvulsive therapy as well as pentylenetetrazol (PTZ) and picrotoxin induced seizures [30]. When administered to rabbits with a genetic mutation causing audiogenic seizures Δ9-THC caused signs of neurotoxicity but prevented seizures when the rabbits were stimulated with a sound stimulus above their normal seizure threshold range. Conversely, in another breed of rabbits, injection with Δ9-THC induced both neurotoxicity and behavioral seizures in a dosage dependent manner [31].
\nThe results of these studies show that Δ9-THC and its metabolites display anticonvulsant activity in animal models using seizure models with rapidly evoked tonic discharges which mimics certain types of generalized onset seizures in humans. However, in models mimicking focal onset seizures, Δ9-THC and its metabolites seem to display a proconvulsant effect. This is manifested by increasing the activity at the site of the focal lesion and increasing generalized cortical activity [27]. A proconvulsant effect is also seen in models mimicking genetic based generalized epilepsies and absence seizures. Δ9-THC and its metabolites seem to induce hypersynchrony with slowly propagating epileptic discharges [32]. While Δ9-THC showed some potential as an anticonvulsant agent the potential to increase seizure activity along with its neurotoxic and psychotropic side effect profile limited its potential benefit in patients with epilepsy.
\nCBD is a low affinity negative allosteric modulator of CB1R with no psychotropic side effects due to the fact it does not cause activation of CB1R. It modulates the influx of both Ca2+ and Na+ into neurons by binding to human T-type voltage gated Ca2+ channels, Melastatin and Vanilloid type Transient Receptor Potential membrane receptors (TRPM and TRPV) and voltage gated Na+ channels [19]. This decreases neuronal excitability in response to stimulation. CBD has also been shown to inhibit intrasynaptic re-uptake of adenosine as well as activation of neuronal Serotonin, Glycine and Vanilloid receptors [33, 34]. The anticonvulsant effect of CBD is felt to be independent of activation of the endogenous CBR pathways. While the exact mechanism of anticonvulsant activity of CBD remains uncertain it appears to have a poly-pharmacological effect on modulating neuronal excitability.
\nIn the Cobalt induced focal epilepsy rat model CBD had no effect on focal discharges at the lesion site but decreased the frequency of seizures. CBD also blocked the proconvulsant effects in of Δ9-THC [27, 35]. In the limbic seizure rat model CBD decreased the frequency, duration and amplitude of electrically induced after discharges at the site of stimulation in the left subiculum but did not prevent the spread of after discharges from the site of focal stimulation to distal electrodes. It had no apparent effect on generalized cortical excitability. This suggests that in focal models of epilepsy, CBD acts directly on the site of focal seizure onset [27].
\nOther animal studies continued to show the anticonvulsant effect of CBD in both transcorneal electroshock, drug induced and lesional epilepsies. This anticonvulsant effect was seen when a single intraperitoneal (i.p.) dose of CBD was administered alone but like Δ9-THC it also potentiated the effects of several anticonvulsant medications [33, 36, 37]. While CBD had potent anticonvulsant effect against tonic seizures its effect against clonic seizures was minimal. Consroe et al. hypothesized that this effect was due to the fact that tonic seizures are spread rapidly throughout the brain from a focal lesion via post-tetanic stimulation. Unlike Δ9-THC, CBD suppressed tetanic potentiation in isolated bullfrog ganglia [27]. This coupled with the fact that CBD is effective in preventing 3-Mercaptoproprionic acid (3-MPA) induced seizures suggested that some of the anticonvulsant effect of CBD may result from its ability to increase production of GABA in presynaptic GABAergic neurons [36]. Unlike Δ9-THC, the brain concentrations of CBD correlated well with its anticonvulsant effect in several animal models. This suggests that the anticonvulsant effect of CBD is due to the parent compound and not its metabolites [27].
\nIn summary, CBD was shown to display broad spectrum anticonvulsant activity in a wide range of animal models of epilepsy including generalized seizures caused by electroshock and GABA inhibiting drugs and focal seizures induced by placement of toxic metals on the cortex. It however had no effect on models of generalized absence seizures [38]. CBD also blocked kindling of a second epileptic focus [36]. Even at high doses it failed to cause any behavioral or cognitive side effects in test animals. This would suggest that CBD is a potent anticonvulsant with limited cognitive side effects, making it an attractive potential anticonvulsant in the pediatric population [33, 37].
\nIn addition, Δ9-THC and CBD several other cannabinoids have been evaluated for the potential anticonvulsant activity. These include ∆9-tetrahydrocannibivarin (∆9-THCV) and cannabidivarin (CBDV) which have been shown to have anticonvulsant effects. ∆9-THCV is a non-psychoactive cannabinoid that acts as a CB1R antagonist. In a Mg2+ depleted solution ∆9-THCV decreased the amplitude and duration of abnormal neuronal burst activity. ∆9-THCV potentiated the effects on neuronal bursting of both phenobarbital and valproic acid. In a PTZ rat model ∆9-THCV did not decrease the severity or duration of seizures or seizure mortality. However significantly fewer rats exposed to PTZ that were treated with ∆9-THCV displayed seizures compared to those that were given PTZ alone [39]. Like CBD, CBDV is believed to exert its effects via CB1R independent mechanisms and has limited neurotoxicity [40]. CBDV has been shown to decrease the amplitude and duration of abnormal bursting in mouse and rat hippocampal slices in in both Mg2+ depleted solution and solution to which 4-aminopyridine (4-AP) has been added. CBDV also significantly decreased the number of seizures seen in in vitro MES and audiogenic seizure models in mice and PTZ induced seizures in rats. Unlike CBD, CBDV also prolonged the latency of seizure induction in a dose dependent manner. Administration of CBDV had no effect on motor performance in mice regardless of the ode administered [41]. The terpenes, which are another class of compounds found in cannabis, also possess a wide range of pharmacological activity on the mammalian nervous system at very low concentrations. Individually, these terpenes have not been assessed in patients with epilepsy [42, 43].
\nThe combinatorial effect of the chemical components of cannabis has been postulated wherein cannabis whole plant extracts may benefit from ‘entourage’ effects to yield greater effectiveness than treatment with a purified cannabinoid [42, 44]. This is supported by preclinical studies. In the
The use of cannabis as a treatment for a variety of ailments in eastern and Mediterranean cultures over the last several millennium has been well documented [47]. The first description of the use of cannabis to treat seizures came from Dr. W. O’Shaugnessy who while working in India reported its successful use to treat seizures in an infant [48]. Following this, cannabis extracts became widely used throughout Europe and North America as an accepted treatment for epilepsy [49]. Following prohibition and with the introduction of other anticonvulsants, cannabis fell out of use as a treatment for epilepsy in western cultures.
\nDuring the mid-twentieth century, several reports on the effect of recreational cannabis consumption surfaced with contrasting effects. Several case reports described patients having decreased seizure frequency following the consumption of cannabis [50]. Cannabis consumption was also shown to be protective against first unprovoked seizures. In adult males who smoked cannabis in the last 90 days, the odds of having a first unprovoked seizure was 0.38 compared to adult males who never consumed cannabis [51]. Conversely, a patient with a history of epilepsy who had been seizure free for several months on medication was reported to have had an exacerbation of seizures following the consumption of cannabis [52].
\nIn 1978, Mechoulam et al. reported their double blinded placebo-controlled study of CBD used as an add-on therapy in patients with refractory focal onset seizures. Of the four patients who took CBD two were seizure free for the 3 months of the study while another had partial improvement. None of the five patients who took placebo had any improvement in their seizures [53]. Cunha et al. reported the results of their study investigating the potential of CBD in patients with refractory temporal lobe epilepsy. In the first phase of the study, healthy adult volunteers were randomized to receive either placebo or CBD at 3 mg/kg/day for 30 days. Of 8 volunteers receiving CBD, 2 reported somnolence otherwise no adverse effects were reported. In the second phase, 15 adult patients with drug-resistant temporal lobe epilepsy were randomized to receive either placebo or CBD (up to 300 mg/day) for a period of 18 weeks in a double-blinded manner. Four of 8 patients dosed with CBD had complete improvement while three had partial improvement. No adverse effects were noted in patients given CBD [54].
\nTwo further studies showed no significant difference in seizure reduction with the addition of CBD as an adjunctive therapy. However, in one study patients were given CBD at a dose of 300 mg/day and their plasma CBD levels were maintained at 20–30 ng/ml. Subsequently one participant who had no difference in their seizure frequency was placed on CBD at a higher dose of up to 1200 mg/day. CBD plasma levels were higher averaging 150 ng/ml. This patient had a significant decrease in their seizure frequency suggesting that higher doses of CBD (and higher plasma levels) were required for seizure control [55].
\nIn recent years there has been a public perception that cannabis is a potent, natural, and safe alternative therapy for epilepsy. This has driven the demand for and use of cannabis and its derived products to treat epilepsy especially in those patients whose seizures are medically intractable. Coupled with the media exposure showing examples of the apparent miraculous effects of CBD oil in select epileptic patients, treating physicians have struggled to balance the patient demand for cannabis products and the need for studies to determine their, efficacy, dosing, side-effect profile, and indication. To that end, there have been multiple studies, predominantly in children, looking into these clinical questions. Unfortunately, the overwhelming majority of these studies have been retrospective, unblinded, and uncontrolled resulting in their being hampered by various forms of bias and potential placebo effect. Despite the plethora of published research on this topic, questions still remain on the use of cannabis in epilepsy.
\nIn this section, we will review the limitations of the studies, the studies using artisanal and CBD enriched cannabis herbal extracts (CHE), the studies using highly purified pharmaceutical grade CBD, and a meta-analysis of the CBD studies.
\nThe widespread use of cannabis and the effect of bias are highlighted in various published surveys. McLachlan performed a survey in London, Ontario, Canada, in which more than 60% of patients declared that cannabis was effective for their seizures and stress levels [56]. Ladina et al. reported a case series of 18 patients who all found medicinal cannabis very helpful for seizure control and improvement of mood disorder [57]. By contrast, Press had reported a significant discrepancy in reported responder rate between preexisting Colorado residents and those who moved to Colorado to obtain cannabis to treat their child’s epilepsy (22 vs. 47%) suggesting there is a significant perception bias among these children’s caregivers as to the therapeutic benefits of cannabis [58]. Physician bias may also play a role as a recent survey by Mathern showed contrasting opinions about CBD between neurologists and the general public. In his study, a minority of epileptologists and general neurologists said that there were sufficient data safety (34%) and efficacy data (28%) and only 48% would advise using medical cannabis and only in severe cases of epilepsy. Conversely, nearly all patients and the general public responded that there was sufficient safety (96%) and efficacy (95%) data, and 98% would recommend cannabis in cases with severe epilepsy [59].
\nGiven the present approved indications for medical coverage, the high cost of pharmaceutical grade CBD products, and the illegal status of cannabis in some countries and US states, the overwhelming majority of patients will at this time be using CBD oil extracts or artisanal products. In many jurisdictions these products are unregulated and therefore their content and consistency are uncertain and can vary. In Australia, where medical use of cannabis is highly restricted, Suraev reported that in parents treating their children with “illicit” cannabis extracts, the majority of extract samples used by the families contained low concentrations of cannabidiol, while Δ9-THC was present in nearly every sample [60]. These findings highlighted the profound variation in the illicit cannabis extracts being used. Studies examining the use of artisanal and CBD oil extracts therefore could have had uncertain and inconsistent amounts of cannabinoids. This inconsistency in combination the inherent problems of retrospective studies, make the findings of these studies questionable; moreover, none of published studies included serum CBD levels.
\nTo date, there are few prospective, double blind, placebo-controlled studies which all only examined the use of the highly purified, pharmaceutical grade CBD (Epidiolex). None involved artisanal CBD or the CBD oil extracts.
\nWhile keeping the limitations of the studies examining artisanal and CBD oil extracts in epilepsy in mind, most of these studies did find that CBD oil extracts are effective in reducing seizures and improving quality of life.
\nTzadok reported out of 74 children being treated with a 20% CBD and 1% Δ9-THC CHE, 89% reported reduction in seizure frequency with only 43% of patients having a >50% reduction in seizures. Five patients reported aggravation of seizures leading to withdrawal from the study. Improvement in behavior and alertness, language, communication, motor skills and sleep were noted. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in five patients. The CBD dosing ranged from 1 to 20 mg/kg/day with 83% taking <10 mg/kg/day [61].
\nSimilarly, Porcari retrospectively studied the efficacy of artisanal CBD preparations in children with epilepsy. The study also included a subgroup comparison to determine if the addition of clobazam was related to any beneficial effects of CBD. Overall, the addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The difference in effect between CBD alone and CBD with clobazam was not statistically significant. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. The average dose of CBD was 2.9 mg/kg/day in the CBD group and 5.8 mg/kg/day in the CBD and clobazam group [62].
\nMcCoy et al. performed a prospective open label study using a 2:100 Δ9-THC:CBD CHE in 20 children with Dravet syndrome. The dose of CBD ranged from 7 to 16 mg/kg/day (mean 13.3 mg CBD/kg/day). They reported that during the 20-week intervention period the median monthly reduction in motor seizures was 70.6%. The CHE also resulted in improvements in quality of life measures and spike index on electroencephalogram (EEG). Adverse events during the titration period included somnolence, anorexia and diarrhea [63].
\nThe Cannabinoid Research Initiative of Saskatchewan is currently conducting a Canadian, multicenter, prospective, open-label, dose-escalation phase 1 trial entitled Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E). The source of the CBD oil is consistent with a single batch of 1:20 Δ9-THC:CBD CHE used for all study participants. Concentrations of the cannabinoids in the CHE were confirmed through Health Canada Quality Assurance and Good Manufacturing Practices (GMP) certification [64]. Preliminary data showed that all 6 participants had improvements in seizure frequency, Quality of Life in Childhood Epilepsy (QOLCE) and EEG rating scores—with three participants showing continued improvements in these measures after the oil extract was discontinued. In addition, serum CBD levels suggested linear dose independent pharmacokinetics in all but one participant. In most participants, serum Δ9-THC concentrations remained lower than what would be expected to cause intoxication even at the maximum dose of oil extract. None of the participants displayed any evidence of Δ9-THC intoxication clinically throughout the study. Preliminary data suggests that an effective and well-tolerated CBD initial target dose of 5–6 mg/kg/day is effective and well tolerated when a 1:20 Δ9-THC:CBD CHE is used. In addition, the serum concentration of CBD follows dose-independent linear pharmacokinetics for most participants, although non-linear pharmacokinetics might occur but requires confirmation. Continued improvement in seizure frequency and QOLCE following the discontinuation of CHE suggest a possible enduring anticonvulsant effect [65].
\nWith the production of a highly purified, pharmaceutical grade CBD (Epidiolex), studies could now be performed with a CBD source of greater reliability. Although potential bias remained, better clinical studies had been performed.
\nDevinksy published an open label trial in patients aged 1–30 with severe, intractable, childhood-onset, drugs resistant epilepsy. All patients were receiving their regular anti-epileptic drugs. Patients were given CBD at 2–5 mg/kg/day, titrated over a period of 2 weeks till intolerance or to a maximum dose of 25 mg/kg to 50 mg/kg/day. The main objective of the study was to establish safety and tolerability of CBD and the primary end point was the median percentage in the mean monthly frequency of motor seizures at 12 weeks. This study included mainly patients with Dravet and Lennox-Gastaut syndromes. One hundred and sixty-two patients were enrolled. A significant high rate of adverse events was reported in 128 patients (79%). The most common were somnolence (n = 41 [25%]), decreased appetite (n = 31 [19%]), diarrhea (n = 31 [19%]) and fatigue (n = 21 [13%]). This high rate of side effects (many of which were seen during the titration period) suggests that too rapid a titration rate may predispose toward side effects. The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) at 12 weeks of treatment. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7) [66].
\nFrom this same cohort, Rosenberg et al. reported that caregivers of 48 patients indicated an 8.2–9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global quality of life (QOL). Interestingly, these differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure reducing effects [67].
\nDevinsky et al. later performed a double blind, placebo-controlled trial in patients with Dravet syndrome including 120 children and young adults using Epidiolex with a CBD dosage of 20 mg/kg/day. The median frequency of convulsive seizures per month decreased from 12.4 (baseline) to 5.9 with CBD, as compared with a decrease from 14.9 (baseline) to 14.1 with placebo (adjusted median difference between cannabidiol vs. placebo was −22.8% points [CI], −41.1 to −5.4; p = 0.01). The percentage of patients who had at least a 50% reduction in convulsive seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93–4.30; p = 0.08). This study shows an overall benefit of CBD over placebo but also a large placebo effect in the control group [68].
\nAnother trial that assessed the efficacy of Epidiolex in reducing atonic seizures in patients with Lennox-Gastaut syndrome. In this double blind, placebo-controlled trial, a total of 225 patients were enrolled, 76 patients were assigned to a treatment group (20 mg/kg/day CBD) and 76 to the placebo group. The median percent reduction from baseline in monthly atonic seizure frequency during the treatment period was 41.9% in the treatment group vs. 21.8% in the placebo group. As with the other studies assessing Epidiolex, the most common adverse events among the patients in the treatment groups were somnolence, decreased appetite, and diarrhea [69].
\nA recent systematic review assessed the safety and efficacy of pharmaceutical grade CBD in pediatric onset drug resistant epilepsy with outcome measures including 50% seizure reduction, complete seizure freedom, improved QOL. A total of 36 studies were identified including 6 randomized controlled trials and 30 observational studies. Overall CBD at a dose of 20 mg/kg/day was more effective than placebo in reducing seizure frequency by 50% (Relative Risk 1.74: 1.24–2.43). For one patient to achieve a 50% reduction in seizures the number of patient needed to treat was 8. In pooled data of 17 of the observational studies CBD at 20 mg/kg/day resulted in 48.5% of patients achieving a 50% reduction in seizures (95% CI: 39.0–58.1%) while pooled data from 14 observational studies showed 8.5% of patients became seizure free (95% CI: 3.8–14.5%). Quality of life improved in 55.8% of patients (95% CI: 40.5–70.6%) while serious adverse events related to treatment with CBD was very low at 2.2% of patients (95% CI: 0.0–7.9%). From this data, the authors concluded that pharmaceutical grade CBD may reduce seizure frequency but other randomized controlled trials examining a more diverse group of epilepsy syndromes and other cannabinoids was needed [70].
\nTo date, the evidence to support the use of cannabis in adults is minimal. STAR 1 is a phase 2A, randomized, double blind, placebo-controlled study that evaluated the safety and efficacy of synthetic transdermal CBD in adult patients with focal epilepsy. In this study 174 patients were randomized to receive either 195 mg CBD, 390 mg CBD or placebo via a transdermal patch. Patients who completed the 12-week study were able to continue into the 24-month open-label extension STAR 2 study (n = 171). In as of yet published data from these trials there was an increase in efficacy of transdermal CBD over 18 months. Median percentage change in seizure rates was −25% at 3 months, −40% at 6 months, −48% at 9 months, −52% at 12 months, −57% at 15 months and −55% at 18 months. The transdermal patch was well tolerated. Serious adverse events were as follows: seizures (n = 2) and increased anxiety (n = 1); one death was reported after the 15 month visit. In addition, no significant elevations in alanine aminotransferase and aspartate aminotransferase levels >3 times upper limit of normal were seen [71].
\nIn comparing cannabis derived treatments to standard therapies, it is worthwhile to note that the STICLO group examining the effects of stiripentol in Dravet patients in a double blind randomized placebo controlled study showed that 15 (71%) patients had >50% seizure reduction (including nine free of clonic or tonic-clonic seizures) compared to only one (5%) on placebo (none were seizure free; stiripentol 95% CI 52.1–90.7 vs. placebo 0–14.6). Stiripentol’s responder rate is therefore suggested to be superior to Epidiolex with a far lower placebo responder rate [72]. Similarly, in a double-blind, randomized, placebo-controlled trial of the anti-epileptic drug rufinamide in patients with Lennox-Gastaut syndrome, the median percentage reduction in total seizure frequency was greater in the rufinamide therapy group than in the placebo group (32.7 vs. 11.7%, p = 0.0015). There was also a difference (p < 0.0001) in tonic-atonic (“drop attack”) seizure frequency with rufinamide (42.5% median percentage reduction) vs. placebo (1.4% increase). These findings are comparable with the results with Epidiolex. One also has to keep in mind that the median reduction of atonic seizures in the placebo group was markedly higher with the Epidiolex study suggesting potential bias [73].
\nOf note, the results from the study by McCoy et al. and the preliminary data from CARE-E study showed a much higher responder rate than those with pharmaceutical grade CBD. This apparent superiority of a CHE containing Δ9-THC would be in keeping with the proposed entourage effect in which the various cannabinoids can act synergistically with one another [42, 44].
\nThe cannabinoids found in cannabis appear to offer a unique pharmacological mode of action in the treatment of epilepsy. This, combined with the apparent low risk of serious side effects, makes cannabis and an attractive potential option for patients with treatment resistant epilepsy.
\nCurrently, there is a large public perception that cannabis products are superior to and safer than conventional anti-epileptic medications especially in treating patients with Dravet syndrome and other pediatric onset epileptic encephalopathies. Based on interpretation of the available data, the authors feel that cannabis based therapies show promise in the treatment of children with treatment resistant epilepsies. While the studies to date assessing cannabis based therapies for the treatment of epilepsy have been encouraging, they should be interpreted with caution. At this time, the long-term adverse effects, the indicated epilepsy and seizure types suitable for treatment with cannabis, the dosing of CBD and other cannabinoids, remain unknown. Also, there is minimal data regarding the pharmacokinetics of the cannabinoids especially in children and when used in patients with multiple concomitant medications. Moreover, the existing studies are limited with the majority of them being retrospective and subject to bias, possible placebo effect, and other limitations.
\nAs such, further studies assessing the safety and efficacy of cannabis based therapies in both adults and children are urgently needed. The authors recommend that these studies start with well-designed dose finding studies that include age stratified pharmacokinetic analysis followed by larger scale clinical trials. When faced with physicians that are reluctant to authorize cannabis based products due to a lack of high quality safety and efficacy data, parents who are desperate to help their children are then forced to turn to unregulated suppliers of cannabis. This puts their children at risk of harm and themselves in legal jeopardy.
\nPurpose statement: This chapter explores the role of cannabis-based therapies in the treatment of children and adults with epilepsy.
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Verification of the element has been made by comparing the finite element results with the analytical solutions available in the literature.",book:{id:"3204",slug:"effective-and-sustainable-hydraulic-fracturing",title:"Effective and Sustainable Hydraulic Fracturing",fullTitle:"Effective and Sustainable Hydraulic Fracturing"},signatures:"Zuorong Chen",authors:[{id:"166734",title:"Dr.",name:"Zuorong",middleName:null,surname:"Chen",slug:"zuorong-chen",fullName:"Zuorong Chen"}]},{id:"44711",title:"Fractures and Fracturing - Hydraulic fracturing in Jointed Rock",slug:"fractures-and-fracturing-hydraulic-fracturing-in-jointed-rock",totalDownloads:5681,totalCrossrefCites:12,totalDimensionsCites:19,abstract:null,book:{id:"3204",slug:"effective-and-sustainable-hydraulic-fracturing",title:"Effective and Sustainable Hydraulic Fracturing",fullTitle:"Effective and Sustainable Hydraulic Fracturing"},signatures:"Charles Fairhurst",authors:[{id:"166474",title:"Dr.",name:"Charles",middleName:null,surname:"Fairhurst",slug:"charles-fairhurst",fullName:"Charles Fairhurst"}]},{id:"44661",title:"Quantitative Evaluation of Completion Techniques on Influencing Shale Fracture ‘Complexity’",slug:"quantitative-evaluation-of-completion-techniques-on-influencing-shale-fracture-complexity-",totalDownloads:3824,totalCrossrefCites:8,totalDimensionsCites:11,abstract:null,book:{id:"3204",slug:"effective-and-sustainable-hydraulic-fracturing",title:"Effective and Sustainable Hydraulic Fracturing",fullTitle:"Effective and Sustainable Hydraulic Fracturing"},signatures:"N. 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