The Human Brain
The human brain is the central commanding organ of the body’s nervous system. It is also the most complex organ; it consists of a network of billions of nerve cells (neurons), glial cells and blood vessels. Sensory organs all send signals to the brain, which in turn would translate them to output signals to different muscles. In structure, the human brain is similar to the brain of any mammal, but in size, it is most significant in the human. It weighs under 2 kilograms making it up to 2 percent of the total body weight.10,11
The most extensive section of the brain is the cerebrum and is divided into two hemispheres, right and left. The outermost layer of the cerebrum is called the cerebral cortex, a thick layer of neural tissues consisting of four lobes, frontal, parietal, temporal and occipital. Compared to other mammals the human cerebral cortex is enlarged and is the center of complex thought. Each lobe is responsible for specific functions, for instance, visual processing occurs in the occipital lobe near the rear of the skull. Languages and sound management all happen in the temporal lobe, which also includes the hippocampus associated with memory and the amygdala associated with emotion. The frontal lobe determines cognitive functions and voluntary movement control. Sensory information such as temperature, touch, movement, and taste are all processed in the parietal lobe.10,11
The two hemispheres of the brain right and left each perform different tasks and are responsible for the different sides of the body. The right hemisphere correlates with creativity and arts and also dominates the left side of the body. The left hemisphere is affiliated with logic and controls the right side of the body. The brainstem is the central trunk that forms the spinal cord at its bottom and connects to the rest of brain above; the brain stem includes the medulla oblongata, pons, and midbrain. Functions such as cardiac and respiratory, and regulation of sensory and motor aspects of the central nervous system are all managed at the brain stem. Cannabinoid receptors in the brain stem are negligible in terms of numbers, and therefore external cannabinoids cannot affect the cardiorespiratory drive. At the bottom of the brain beneath the cerebrum and above the brainstem is the cerebellum which is essential in motor control such as balance, coordination, posture, and speech.
The neuromodulatory lipids and receptors in the brain are part of the endocannabinoid system that manages a series of physiological processes in the brain and the peripheral nervous system, both of which are crucial for human health and life.10,11
Amyotrophic Lateral Sclerosis (ALS)
It starts off with muscle weakness or stiffness, then escalates to loss of strength, the ability to speak, eat, move and eventually even breathing, this is the typical development of ALS, amyotrophic lateral sclerosis. ALS is classified under motor neuron diseases; the group has neurodegeneration and death of motor neurons in common. These conditions of ALS are related to an imbalance of both the inflammatory response and the Gamma-Aminobutyric Acid (GABA) which is a primary neurotransmitter acting to calm the central nervous system.
Preclinical research has shown that CBD suppresses inflammatory response by preventing the release of cytokines and chemokines, which are pro-inflammatory. Cannabidiol is also useful in restraining oxidative and nitrosative stress; damages that occur from reactive nitrogen (RNS) and oxygen (ROS) species. It also regulates nitric oxide synthase and decreases the creation of RNS and ROS.79,80
Glutamate neurotransmitters if excessively stimulated can damage or kill nerve cells; this excitotoxicity can be limited by restricting the release of glutamate. Cannabinoids have this effect on glutamate and CBD specifically has been found to promote the effects of GABA. Results of in vivo studies agree that cannabinoids may have beneficial properties towards ALS; they can act as neuroprotective agents.14
The inception of ALS could be deferred through treatment with CBN cannabinol, which is similar to CBD in its non-toxicity but differs in its residual affinity to CB1 receptors.81
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One of the most common forms of dementia, a disease associated with loss of cognitive abilities such as memory, is Alzheimer’s Disease. More than half dementia cases are Alzheimer’s. It is a disorder of neurodegenerative features that impact cerebral neurons, consequently leading to severe conditions that make daily tasks a challenge. Besides memory loss, these conditions also include behavioral and mood changes. The early symptoms start off in the hippocampal nerve cells, and newly learned information becomes difficult to remember. As the disease progresses deeper within the brain reaching the cerebral cortex, the symptoms worsen to include a decline in language skills, disorientation and mood and behavioral changes.26
Alzheimer’s is a complex neurodegenerative disease, which corresponds to a CECD; possibly the leading cause is a result of the hyperactivity of Amyloid beta that warrants an inflammatory response. Amyloid beta is the main component that forms Amyloid plaque; a protein that forms a sticky buildup engulfing nerve cells, and is common in Alzheimer’s disease. Cannabidiol, through in vivo studies has shown prospects of degrading Amyloid plaque through peroxisome proliferator-activated receptor (PPAR) stimulation. The study further supports the use of CBD in the treatment of cognitive deficits in advanced stages of Alzheimer’s; this role is also supported by the US patent 6-630-507. CBD has a promising prospect as a preventative measure and treatment for Alzheimer’s diseases.1, 3, 7-9, 15, 21, 23, 28, 36, 80, 82
The loss of dopamine-producing cells results in motor function retrogression over time ultimately resulting in the neurodegenerative disorder known as Parkinson’s disease. Dopamine is a messaging substance that communicates between the substantia nigra and the corpus striatum; chiefly to regulate smooth and controlled movements. Once levels of dopamine have fallen, communication ceases to be effective. Symptoms of Parkinson’s disease are related to the reduction of dopamine and include tremors, stiffness, bradykinesia, impaired balance, slowness, anxiety, depression, and dementia. By the time that these symptoms have appeared patients would have lost up to 80% of the dopamine-producing cells in their brain.
Researchers did not determine the exact cause of this disease, yet studies point towards genetic predetermination as well as environmental factors. Parkinson’s progression is linked to genetic CECD; current studies affirm the contribution of inflammation and immunologic dysfunctions in the progression of Parkinson’s. This contribution was found especially applicable to cases where the disease has a delayed onset.
Therapeutic administration of the plant-based cannabidiol can reduce some of the symptoms associated with Parkinson’s as suggested by research. The symptoms that CBD alleviates include tremors, involuntary muscles contractions, psychosis, and depression. Moreover, considering the antioxidant features of CBD and its response modulation effect of both CB1 and CB2 receptors, it can be utilized even to prevent the development of Parkinson’s.1, 3 7, 9, 12, 14-16, 21, 23, 28, 30, 34, 35, 75, 79, 80
Another genetically inherited disease (classified as a genetic CECD) that causes progressive nerve cell degeneration in the brain is Huntington’s disease also known as Huntington’s Chorea. The impact of this disease is broad on functional abilities, usually leading to movement, cognitive and psychiatric disorders. Symptoms appear in patients with the disease during their 40’s, but the condition may emerge at any time.
The early stages of Huntington’s disease show a sharp decline in CB1 receptors in the basal ganglia which is interconnected strongly with the cerebral cortex; this also affects the regulatory system connected to CB2 receptors. The reduction in CB1 receptor density supports Cannabinoids role in the progression of this neurodegenerative disease; cannabidiol has shown promising properties that could hinder this progression. It can also alleviate some of the symptoms such as associated pains and anxiety relief. Additionally, the neuroprotective and antioxidants characteristics of CBD have the potential of slowing down the emergence of the severe symptoms of the disease.1, 3, 7, 12, 15, 16, 25, 30, 35-37, 52, 54, 56, 75, 80
Cerebral Ischemia and Stroke
When the brain’s vascular circulatory system is interrupted, the flow of blood drops leading to damage to the cerebral tissue; this damage is cerebral ischemia more commonly described as a stroke. Several elements can cause cerebral ischemia, one of the most common is atherosclerosis, a condition where cerebral thrombosis or embolism interrupts blood flow leading to direct cell damage. Other causes of cerebral ischemia include but are not limited to, hypertension, diabetes, and nicotine use.
Cerebral ischemia is an acquired CECD case, which has previously resulted in the dysfunction of CB1 and CB2 receptors and reduced circulating cannabinoid density. In vivo experiments concluded that the therapeutic administration of CBD up to four hours after such a stroke has some benefits. CBD would reduce inflammation and decrease blood pressure through encouraging blood vessel dilation; residual motor deficits would also diminish.
Regarding disease prevention, CBD properties such as antioxidant, anti-inflammation and neuroprotective have promising prospects for people that are at risk of cerebral ischemia. The cerebral function is enhanced through increasing the density of circulating cannabinoids and restoring receptors CB1 and CB2 functions.10, 14, 18, 21, 23, 25, 27, 29, 31, 32, 35, 36, 37, 53, 55, 57
A protective myelin sheath surrounds nerve fibers in the central nervous system (CNS), which also assists the nerves in conducting quick and efficient electrical signals. In cases of Multiple Sclerosis (MS), an autoimmune disease that attacks the CNS, the myelin sheath is absent leaving scared plaques or lesions behind. Without the protective myelin, the lesions worsen until the nerve fibers lose their ability to conduct electrical impulses.67
MS affects the central control of all actions; the symptoms can, therefore, appear in any part of the body. The severity of the symptoms also ranges from unnoticeable to extremely rigorous. Some of the overall symptoms include muscle weakness, paralysis, numbness and tingling, visual disturbances. The effects of MS can lead to bladder or bowel dysfunction, muscle spasms and tremors.59, 61, 62
Multiple clinical studies have shown evidence of the CBD’s effectiveness as a treatment for MS patients; CBD is antioxidative, anti-inflammatory, muscle relaxing, neuroprotective and anti-intoxicating. For reducing pain and spasticity, CBD is handy; the therapeutic administration of CBD in early stages of MS may prevent its development. CBD can alleviate the neuroinflammatory response in the cerebral cortex, and the myelin cell destruction avoided.4, 6, 7, 12, 14, 15, 17, 19, 21-24, 26-28, 31, 37, 39, 52, 54, 55, 58-67, 76, 78
Schizophrenia is a psychiatric disorder that usually emerges in late adolescence or at the beginning of adulthood. The disorder is distinguishable by abnormalities in social behavior, delusions, hallucinations, cognitive difficulties, reduced emotional expression and social interactions, and others.
The cause of Schizophrenia has been deemed by researchers to be a combination of genetical inheritance, drug-induced and other factors such as the environmental and social. Schizophrenia is a genetic and drug acquired CECD.
By measuring anandamide in cerebrospinal fluid in acute schizophrenic patients, studies have found the levels of anandamide are very elevated in comparison to natural levels. This increase in anandamide is likely the brain’s instinctive effort to eliminate disease induced stress; a result of deficiencies in CB1 receptors that prevent it from binding. CBD administration can fix this deficiency in CB1 receptors by activating more receptors for anandamide to bind to, hence also stopping its degradation.
Therapeutic administration of plant-based cannabidiol in schizophrenia patients has shown results of anxiety and hallucination relief, and behavioral modification.5, 6, 14, 16, 17, 21, 22, 33, 35, 37, 40-48, 68, 75
Seizure disorder or epilepsy is in the top four neurological disorders. Recurrent and unprovoked seizures are typical of this disorder; suggested as a brain injury that causes them spontaneously. The severity and type of seizure differ and at times can progress seriously and also be co-occurred with cognitive and behavioral effects.
Epileptogenesis is a process by which a non-epileptic brain develops epilepsy; the gradual process occurs in symptomatic epilepsy, in which an identifiable brain lesion causes seizures. It results from acute brain insults such as traumatic brain injury, stroke, or infection. Epileptogenesis is a latent period that occurs between the event that causes epilepsy and the first spontaneous seizure. In epileptogenesis, a pattern of events occurs on molecular and cellular levels causing neurons to fire in a disorganized mode, producing in seizures.22, 49, 50, 74
A phytocannabinoid treatment during this latency period has the potential of preventing or modifying the epileptogenesis process, increasing the chances for a better quality of life. Research concurs with the therapeutic and preventive effects of CBD on many epileptic patients. CBD was found to reduce tenacious seizures and improve cognitive function. Enhanced CB receptor response with an increase of cannabinoid density corresponds with neurological enhancement in epilepsy and support the use of CBD for seizure disorders.3, 4, 6, 7, 12, 22, 24, 29, 30, 35, 37, 42, 49, 50, 55, 56, 65, 74
Migraines are exceptionally prevalent chronic neurological disorders affecting a billion people worldwide. Typically the symptoms include recurring sharp throbbing pains affecting one side of the brain and in some cases both sides. The pains are accompanied by disabling symptoms, visual disturbances, nausea, vomiting dizziness, extreme sensitivity to sound, light, touch, smell and tingling or numbness. In some cases, the visual disturbances can cause an aura that usually precedes a migraine.
Migraines are CECD and can be acquired, genetic or idiopathic autoimmune. The severe pains associated with migraines are a result of dysfunctional CB1 receptors in both the cerebral cortex and the brainstems trigeminal nucleus, rendering them incapable of neurotransmitting and triggering inflammatory responses. The neurovascular inflammation can be reduced by CBD administration that would reduce pain in acute cases, and would assume a preventative role in chronic migraines.2, 4, 25, 66, 67
Depression and Anxiety
Depression and anxiety disorders are diverse, but people suffering from depression regularly encounter symptoms similar to an anxiety disorder, such as nervousness, irritability, sleep disruptions and concentrating difficulties. CBD therapy is a suitable candidate for the treatment of both disorders.
Depression is distinguishable by the following symptoms, an intense sadness or the loss of interest and pleasure in most usual activities, decrease or increase in appetite, insomnia, constant fatigue and cognitive difficulties, such as, diminished ability to think, concentrate and make decisions. Such cases link to the CB1 receptor activity in the anterior cingulate cortex and subgenual cingulate. CB2 receptors have also been suggested to be dysfunctional in chronic depression cases.
Both disorders depression and anxiety respond to treatment by CBD; increasing cannabinoid signaling will have comparable mechanisms to conventional antidepressant drugs. Studies support the promising treatment possibilities of CBD for depression and anxiety patients.4, 11-13, 20, 25, 48, 51, 69, 71-73
- Cannabinoid receptors and their ligands, Pertwee, R.G. et al. Prostaglandins, Leukotrienes and Essential Fatty Acids , Volume 66 , Issue 2 , 101 – 121 available at https://www.ncbi.nlm.nih.gov/pubmed/12052030
- Vincenzo Di Marzo, ‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance, Biochimica et Biophysica Acta (BBA) – Lipids and Lipid Metabolism, Volume 1392, Issues 2–3, 1998, Pages 153-175, available at https://www.sciencedirect.com/science/article/pii/S0005276098000423?via%3Dihub
- Grotenhermen, F. Clin Pharmacokinet (2003) 42: 327. https://doi.org/10.2165/00003088-200342040-00003
- Russo E. B, Neuro Endocrinol Lett. 2004 Feb-Apr;25(1-2):31-9. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Available at https://www.ncbi.nlm.nih.gov/pubmed/15159679
- Scott Shannon, MD and Janet Opila-Lehman, ND, Integr Med (Encinitas). 2015 Dec; 14(6): 31–35. Cannabidiol Oil for Decreasing Addictive Use of Marijuana: A Case Report, available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718203/
- CBD-enriched medical cannabis for intractable pediatric epilepsy Tzadok, Michal et al. Seizure – European Journal of Epilepsy , Volume 35 , 41 – 44, available at https://www.ncbi.nlm.nih.gov/pubmed/26800377
- Behera, Atanu kumar & Shah, Samip & Barik, Bhakti Bhusan. (2013). Development and enhancement of entrapment efficiency of isoniazid loaded poly-ε-caprolactone nanoparticle. Der Pharmacia Lettre. 5. 43-50. Available at https://www.scribd.com/document/291320806/Development-and-Enhancement-of-Entrapment-Efficiency-of-Isoniazid-Loaded-Poly-caprolactone-Nanoparticle
- Gertsch, J. (2017) Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation?. British Journal of Pharmacology, 174: 1464–1483, available at https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.13676
- Lipina, C., & Hundal, H. S. (2017). The endocannabinoid system: no longer anonymous in the control of nitrergic signalling? Journal of Molecular Cell Biology, 9(2), 91-103, available at https://discovery.dundee.ac.uk/en/publications/the-endocannabinoid-system-no-longer-anonymous-in-the-control-of-
- Scarabino, T., Salvolini, U. Atlas of Morphology and Functional Anatomy of the Brain. Springer-Verlag Berlin Heidelberg, (2006).
- Leslie Iversen; Cannabis and the brain, Brain, Volume 126, Issue 6, 1 June 2003, Pages 1252–1270, available at https://academic.oup.com/brain/article/126/6/1252/330602
- Roger G. Pertwee, Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities, Phil. Trans. R. Soc. B 2012 367 3353-3363; available at http://rstb.royalsocietypublishing.org/content/367/1607/3353.long
- Elphick MR, Egertová M. The neurobiology and evolution of cannabinoid signalling. Philosophical Transactions of the Royal Society of London Series B. 2001; 356 (1407): 381-408. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1088434/
- Croxford, J.L. Therapeutic Potential of Cannabinoids in CNS Disease. CNS Drugs (2003) 17: 179. Available at https://link.springer.com/article/10.2165/00023210-200317030-00004#citeas
- George W. Booz, Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress, Free Radical Biology and Medicine, Volume 51, Issue 5, 2011, Pages 1054-1061, ISSN 0891-5849, available at: http://www.sciencedirect.com/science/article/pii/S0891584911000116
- Francisco Espejo-Porras, Javier Fernández-Ruiz, Roger G. Pertwee, Raphael Mechoulam, Concepción García, Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors, Neuropharmacology, Volume 75, 2013, Pages 155-163, ISSN 0028-3908, available at: http://www.sciencedirect.com/science/article/pii/S0028390813003419
- C Mbvundula, Estery & Rainsford, Kim & A D Bunning, Rowena. (2004). Cannabinoids in pain and inflammation. Inflammopharmacology. 12. 99-114. Available at https://www.researchgate.net/publication/8444904_Cannabinoids_in_pain_and_inflammation
- Crandall J, Matragoon S, Khalifa Y, M, Borlongan C, Tsai N, -T, Caldwell R, B, Liou G, I, Neuroprotective and Intraocular Pressure-Lowering Effects of (–)Δ<sup>9</sup>-Tetrahydrocannabinol in a Rat Model of Glaucoma. Ophthalmic Res 2007;39:69-75, available at https://www.karger.com/Article/Abstract/99240#
- Barbara Costa, Anna Elisa Trovato, Francesca Comelli, Gabriella Giagnoni, Mariapia Colleoni, The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain, European Journal of Pharmacology, Volume 556, Issues 1–3, 2007, Pages 75-83, ISSN 0014-2999, available at http://www.sciencedirect.com/science/article/pii/S001429990601257X
- ElSohly M.A., Radwan M.M., Gul W., Chandra S., Galal A. (2017) Phytochemistry of Cannabis sativa L.. In: Kinghorn A., Falk H., Gibbons S., Kobayashi J. (eds) Phytocannabinoids. Progress in the Chemistry of Organic Natural Products, vol 103. Springer, Cham. available at https://link.springer.com/chapter/10.1007%2F978-3-319-45541-9_1#citeas
- Deiana, S. (2013), Medical use of cannabis. Cannabidiol: A new light for schizophrenia?. Drug Test. Analysis, 5: 46-51, available at https://doi.org/10.1002/dta.1425
- Maria Roberta Cilio Elizabeth A. Thiele Orrin Devinsky, The case for assessing cannabidiol in epilepsy, Epilepsia, 55(6):787–790, 2014 https://doi.org/10.1111/epi.12635
- Mia Levite, Nerve-Driven Immunity: Neurotransmitters and Neuropeptides in the Immune System, Springer, Vienna (2012), available at https://link.springer.com/book/10.1007%2F978-3-7091-0888-8#toc
- Wei, Y., Wang, X., Zhao, F., Zhao, P., & Kang, X. (2013). Cannabinoid receptor 1 blockade protects human retinal pigment epithelial cells from oxidative injury. Molecular Vision, 19, 357–366, available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580988/
- Smith SC, Wagner MS. Clinical endocannabinoid deficiency (CECD) revisited: can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2014; 35(3): 198 – 201. Available at https://www.ncbi.nlm.nih.gov/pubmed
- Esposito, G., De Filippis, D., Carnuccio, R. et al. J Mol Med (2006) 84: 253. https://doi.org/10.1007/s00109-005-0025-1
- Liou G, El-Remessy A, Ibrahim A, et al. Cannabidiol As a Putative Novel Therapy for Diabetic Retinopathy: A Postulated Mechanism of Action as an Entry Point for Biomarker-Guided Clinical Development. Current pharmacogenomics and personalized medicine. 2009;7(3):215-222. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955420/
- Sevda Dirikoc, Suzette A. Priola, Mathieu Marella, Nicole Zsürger, Joëlle Chabry,
Nonpsychoactive Cannabidiol Prevents Prion Accumulation and Protects Neurons against Prion Toxicity, Journal of Neuroscience 5 September 2007, 27 (36) 9537-9544, available at http://www.jneurosci.org/content/27/36/9537.long
- Hayakawa, K. , Mishima, K. , Nozako, M. , Hazekawa, M. , Irie, K. , Fujioka, M. , Orito, K. , Abe, K. , Hasebe, N. , Egashira, N. , Iwasaki, K. and Fujiwara, M. (2007), Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor‐independent myeloperoxidase‐inhibiting mechanism. Journal of Neurochemistry, 102: 1488-1496. Available at https://doi.org/10.1111/j.1471-4159.2007.04565.x
- Neife Aparecida Guinaim Santos, Nádia Maria Martins, Flávia Malvestio Sisti, Laís Silva Fernandes, Rafaela Scalco Ferreira, Regina Helena Costa Queiroz, Antônio Cardozo Santos, The neuroprotection of cannabidiol against MPP+-induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson’s disease, Toxicology in Vitro, Volume 30, Issue 1, Part B, 2015, Pages 231-240, ISSN 0887-2333, available at https://doi.org/10.1016/j.tiv.2015.11.004.
- Hind, W. H., England, T. J., and O’Sullivan, S. E. (2016) Cannabidiol protects an in vitro model of the blood–brain barrier from oxygen‐glucose deprivation via PPARγ and 5‐HT1A receptors. British Journal of Pharmacology, 173: 815–825. Available at https://doi.org/10.1111/bph.13368
- Mishima, K. Hayakawa, K. Abe, K. Ikeda, T. Egashira, N. Iwasaki, K. Fujiwara, M. Cannabidiol Prevents Cerebral Infarction Via a Serotonergic 5-Hydroxytryptamine1A Receptor-Dependent Mechanism. Stroke 36, 1071-1076 (2005), available at https://doi.org/10.1161/01.STR.0000163083.59201.34
- Parray, H.A. & Yun, J.W. Cannabidiol promotes browning in 3T3-L1 adipocytes. Mol Cell Biochem (2016) 416: 131. https://doi.org/10.1007/s11010-016-2702-5
- M. H, C. et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: An exploratory double-blind trial. J Psychopharmacol. II, 1088-1098 (2014) available at https://doi.org/10.1177/0269881114550355
- Zuardi, Antonio Waldo. (2008). Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Revista Brasileira de Psiquiatria, 30(3), 271-280. Available at https://dx.doi.org/10.1590/S1516-44462008000300015
- Paul Consroe, Joan Laguna, James Allender, Stuart Snider, Lawrence Stern, Reuven Sandyk, Kurt Kennedy, Karl Schram, Controlled clinical trial of cannabidiol in Huntington’s disease, Pharmacology Biochemistry and Behavior, Volume 40, Issue 3, 1991, Pages 701-708, ISSN 0091-3057, available at https://doi.org/10.1016/0091-3057(91)90386-G.
- Fernández-Ruiz, J., Sagredo, O., Pazos, M. R., García, C., Pertwee, R., Mechoulam, R., & Martínez-Orgado, J. (2013). Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? British Journal of Clinical Pharmacology, 75(2), 323–333. Available at http://doi.org/10.1111/j.1365-2125.2012.04341.x
- Daniela Braida, Simona Pegorini, Maria Vittoria Arcidiacono, Gian Giacomo Consalez, Laura Croci, Mariaelvina Sala, Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils, Neuroscience Letters, Volume 346, Issues 1–2, 2003, Pages 61-64, ISSN 0304-3940, available at https://doi.org/10.1016/S0304-3940(03)00569-X.
- Syed, Y.Y., McKeage, K. & Scott, L.J. Delta-9-Tetrahydrocannabinol/Cannabidiol (Sativex®): A Review of Its Use in Patients with Moderate to Severe Spasticity Due to Multiple Sclerosis .Drugs (2014) 74: 563 – 578. Available at https://doi.org/10.1007/s40265-014-0197-5
- Iseger, Tabitha A. et al. A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophrenia Research, Volume 162, Issue 1, 153 – 161, (2015) available at https://doi.org/10.1016/j.schres.2015.01.033
- Ashleigh L. Osborne, Nadia Solowij, Katrina Weston-Green, A systematic review of the effect of cannabidiol on cognitive function: Relevance to schizophrenia, Neuroscience & Biobehavioral Reviews, Volume 72, 2017, Pages 310-324, ISSN 0149-7634, available at https://doi.org/10.1016/j.neubiorev.2016.11.012.
- Devinsky, O et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55, 791-802 (2014), available at https://doi.org/10.1111/epi.12631
- Schubart, C.D. et al. Cannabidiol as a potential treatment for psychosis, European Neuropsychopharmacology, Volume 24, Issue 1, 51 – 64 (2014), available at https://doi.org/10.1016/j.euroneuro.2013.11.002
- Gururajan, Anand et al. Does cannabidiol have a role in the treatment of schizophrenia? Schizophrenia Research, Volume 176, Issue 2, 281 – 290 (2016) available at https://doi.org/10.1016/j.schres.2016.06.022
- Schier, Alexandre Rafael de Mello, Ribeiro, Natalia Pinho de Oliveira, Silva, Adriana Cardoso de Oliveira e, Hallak, Jaime Eduardo Cecílio, Crippa, José Alexandre S., Nardi, Antonio E., & Zuardi, Antonio Waldo. (2012). Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. Revista Brasileira de Psiquiatria, 34(Suppl. 1), 104-110. Available at https://dx.doi.org/10.1590/S1516-44462012000500008
- Waldo Zuardi, A. et al. A Critical Review of the Antipsychotic Effects of Cannabidiol: 30 Years of a Translational Investigation. Curr. Pharm. Des. 18, 5131-5140 (2012). Available at http://www.eurekaselect.com/102849/article
- Patrik Roser and Ida S. Haussleiter, Antipsychotic-like Effects of Cannabidiol and Rimonabant: Systematic Review of Animal and Human Studies, Current Pharmaceutical Design, volume 18, issue 32, pages 5141-5155, year 2012, issn 1381-6128/1873-4286, available at http://www.eurekaselect.com/node/102850/article
- Justine Renard, Christopher Norris, Walter Rushlow, Steven R. Laviolette, Neuronal and molecular effects of cannabidiol on the mesolimbic dopamine system: Implications for novel schizophrenia treatments, Neuroscience & Biobehavioral Reviews, Volume 75, 2017, Pages 157-165, ISSN 0149-7634, available at https://doi.org/10.1016/j.neubiorev.2017.02.006
- Szaflarski, Jerzy P. et al. Cannabis, cannabidiol, and epilepsy — From receptors to clinical response, Epilepsy & Behavior , Volume 41 , 277 – 282 (2014), availble at https://doi.org/10.1016/j.yebeh.2014.08.135
- Antonio Leo, Emilio Russo, Maurizio Elia, Cannabidiol and epilepsy: Rationale and therapeutic potential, Pharmacological Research, Volume 107, 2016, Pages 85-92, ISSN 1043-6618, available at https://doi.org/10.1016/j.phrs.2016.03.005
- Campos, A. C., Moreira, F. A., Gomes, F. V., Del Bel, E. A., & Guimarães, F. S. (2012). Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philosophical Transactions of the Royal Society B: Biological Sciences, 367(1607), 3364–3378. Available at http://doi.org/10.1098/rstb.2011.0389
- Onintza Sagredo, M. Ruth Pazos, Sara Valdeolivas and Javier Fernandez-Ruiz, Cannabinoids: Novel Medicines for the Treatment of Huntington’s Disease, Recent Patents on CNS Drug Discovery (Discontinued), volume 7, issue 1, pages 41-48, year 2012, issn 1574-8898/2212-3954, available at http://www.eurekaselect.com/node/89300/article
- Tomida, I. et al. Effect of Sublingual Application of Cannabinoids on Intraocular Pressure: A Pilot Study. Journal of Glaucoma. 15(5):349-353, OCT 2006, available at https://insights.ovid.com/pubmed?pmid=16988594#
- Sara Valdeolivas, Valentina Satta, Roger G. Pertwee, Javier Fernández-Ruiz, and Onintza Sagredo, Sativex-like Combination of Phytocannabinoids is Neuroprotective in Malonate-Lesioned Rats, an Inflammatory Model of Huntington’s Disease: Role of CB1 and CB2 Receptors, ACS Chemical Neuroscience 2012 3 (5), 400-406 available at https://pubs.acs.org/doi/10.1021/cn200114w
- Timothy J England, William H Hind, Nadiah A Rasid, Saoirse E O’Sullivan, Cannabinoids in Experimental Stroke: A Systematic Review and Meta-Analysis, Volume: 35 issue: 3, page(s): 348-358 (2015) available at http://journals.sagepub.com/doi/10.1038/jcbfm.2014.218
- Robert B. Laprairie, Amina M. Bagher, Melanie E. M. Kelly and Eileen M. Denovan-Wright, Biased CB1 Signaling in Huntington Disease. Molecular Pharmacology March 1, 2016, 89 (3) 364-375; available at https://doi.org/10.1124/mol.115.101980
- A. J. Hampson, M. Grimaldi, J. Axelrod, D. Wink, Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proceedings of the National Academy of Sciences Jul 1998, 95 (14) 8268-8273; available at https://doi.org/10.1073/pnas.95.14.8268
- Di Marzo, V. and Centonze, D. (2015), Placebo Effects in a Multiple Sclerosis Spasticity Enriched Clinical Trial with the Oromucosal Cannabinoid Spray (THC/CBD): Dimension and Possible Causes. CNS Neurosci Ther, 21: 215-221. Available at https://doi.org/10.1111/cns.12358
- Giulio Podda & Cris S Constantinescu (2012) Nabiximols in the treatment of spasticity, pain and urinary symptoms due to multiple sclerosis, Expert Opinion on Biological Therapy, 12:11, 1517-1531, available at https://doi.org/10.1517/14712598.2012.721765
- Irene Moreno Torres, Antonio J Sanchez & Antonio Garcia-Merino (2014) Evaluation of the tolerability and efficacy of Sativex in multiple sclerosis, Expert Review of Neurotherapeutics, 14:11, 1243-1250, available at https://doi.org/10.1586/14737175.2014.971758
- Jürgen Koehler, Maria P Amato, Celia Oreja-Guevara & Jan Lycke (2013) Clinical case reviews in multiple sclerosis spasticity: experiences from around Europe, Expert Review of Neurotherapeutics, 13:sup2, 61-66, available at https://doi.org/10.1586/14737175.2013.865881
- Vincenzo Di Marzo (2014) Endocannabinoid pathways and their role in multiple sclerosis-related muscular dysfunction, Expert Review of Neurotherapeutics, 11:sup4, 9-14, https://doi.org/10.1586/ern.11.26
- Shaheen E Lakhan and Marie Rowland, Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review, BMC Neurology 2009 9:59, available at https://doi.org/10.1186/1471-2377-9-59
- Zettl, U. K., Rommer, P., Hipp, P., & Patejdl, R. (2016). Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis. Therapeutic Advances in Neurological Disorders, 9 (1), 9–30. Available at http://doi.org/10.1177/1756285615612659
- Pryce, G., Riddall, D.R., Selwood, D.L. et al. J Neuroimmune Pharmacol (2015) 10: 281. Available at https://doi.org/10.1007/s11481-014-9575-8
- Leussink, V. I., Husseini, L., Warnke, C., Broussalis, E., Hartung, H.-P., & Kieseier, B. C. (2012). Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity. Therapeutic Advances in Neurological Disorders, 5(5), 255–266. Available at http://doi.org/10.1177/1756285612453972
- Lara Teare & John Zajicek (2005) The use of cannabinoids in multiple sclerosis, Expert Opinion on Investigational Drugs, 14:7, 859-869, available at https://doi.org/10.1517/135437184.108.40.2069
- Jan Malte Bumb, Frank Enning & F Markus Leweke (2015) Drug repurposing and emerging adjunctive treatments for schizophrenia, Expert Opinion on Pharmacotherapy, 16:7, 1049-1067, available at https://doi.org/10.1517/14656566.2015.1032248
- Baron, E. P. (2015), Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been …. Headache: The Journal of Head and Face Pain, 55: 885-916. Available at https://doi.org/10.1111/head.12570
- Selim R Benbadis, Juan Sanchez-Ramos, Ali Bozorg, Melissa Giarratano, Kavita Kalidas, Lara Katzin, Derrick Robertson, Tuan Vu, Amanda Smith & Theresa Zesiewicz (2014) Medical marijuana in neurology, Expert Review of Neurotherapeutics, 14:12, 1453-1465, available at https://doi.org/10.1586/14737175.2014.985209
- C. H. Ashton P. B. Moore, Endocannabinoid system dysfunction in mood and related disorders, Acta Psychiatrica Scandinavica Volume 124, Issue 4 (2011) available at https://doi.org/10.1111/j.1600-0447.2011.01687.x
- C. H. Ashton, P. B. Moore, P. Gallagher A. H. Young, Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential. Journal of Psychopharmacology Volume: 19 issue: 3, page(s): 293-300 Issue published: May 1, 2005, available at https://doi.org/10.1177/0269881105051541
- Daniela Parolaro, Natalia Realini, Daniela Vigano, Cinzia Guidali, Tiziana Rubino, The endocannabinoid system and psychiatric disorders, Experimental Neurology, Volume 224, Issue 1, 2010, Pages 3-14, ISSN 0014-4886, available at https://doi.org/10.1016/j.expneurol.2010.03.018
- Devinsky, O., Cilio, M. R., Cross, H., Fernandez-Ruiz, J., French, J., Hill, C., … Friedman, D. (2014). Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia, 55(6), 791–802. Available at http://doi.org/10.1111/epi.12631
- AW Zuardi, Jas Crippa, JEC Hallak JP Pinto, MHN Chagas, GGR Rodrigues, SM Dursun, V. Tumas. Cannabidiol for the treatment of psychosis in Parkinson’s disease. Journal of Psychopharmacology, Volume: 23 issue: 8, page(s): 979-983 (2008). Available at https://doi.org/10.1177/0269881108096519
- Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use A Systematic Review and Meta-analysis. JAMA. 2015;313(24):2456–2473. Available at https://jamanetwork.com/journals/jama/fullarticle/2338251
- García, C., Palomo-Garo, C., García-Arencibia, M., Ramos, J., Pertwee, R., & Fernández-Ruiz, J. (2011). Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ9-THCV in animal models of Parkinson’s disease. British Journal of Pharmacology, 163(7), 1495–1506. Available at http://doi.org/10.1111/j.1476-5381.2011.01278.x
- Judith Haas (2014) Pathophysiology, assessment and management of multiple sclerosis spasticity: an update, Expert Review of Neurotherapeutics, 11:sup4, 3-8, available at https://doi.org/10.1586/ern.11.25
- Zarei, S., Carr, K., Reiley, L., Diaz, K., Guerra, O., Altamirano, P. F., … Chinea, A. (2015). A comprehensive review of amyotrophic lateral sclerosis. Surgical Neurology International, 6, 171. Available at http://doi.org/10.4103/2152-7806.169561
- Latha Velayudhan, Erik Van Diepen, Mangesh Marudkar, Oliver Hands, Srinivas Suribhatla, Richard Prettyman, Jonathan Murray, Sarah Baillon and Sagnik Bhattacharyya,Therapeutic Potential of Cannabinoids in Neurodegenerative Disorders: A Selective Review,Current Pharmaceutical Design, volume 20, issue 13, pages 2218-2230, year 2014, issn 1381-6128/1873-4286, available at (http://www.eurekaselect.com/node/111837/article)
- Giacoppo, S., & Mazzon, E. (2016). Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis? Neural Regeneration Research, 11(12), 1896–1899. Available at http://doi.org/10.4103/1673-5374.197125
- Tezel, G., Yang, X., Luo, C., Peng, Y., Sun, S. L., & Sun, D. (2007). Mechanisms of Immune System Activation in Glaucoma: Oxidative Stress-Stimulated Antigen Presentation by the Retina and Optic Nerve Head Glia. Investigative Ophthalmology & Visual Science, 48(2), 705–714. Available at http://doi.org/10.1167/iovs.06-0810