“Relax, eat, sleep, forget and protect”
Towards the end of the 80’s scientist first discovered the endocannabinoid system, a lipid signaling network common amongst all mammals. This network is made up of cannabinoid receptors (CB), endogenous ligands and the enzymes that can make or break them on demand. There are two primary receptors, CB1 these are G-protein-coupled neuromodulating receptors (alters nerve activity through stimuli delivery) found throughout the nervous system and also on end organs like lungs, liver, kidneys, and also on reproductive organs. CB2 receptors are immunomodulating receptors (it stimulates or suppresses the immune system) in the immune tissue, digestive tract, the circulatory system and on hematopoietic cells. Cannabinoid receptors are also in adipocytes and musculoskeletal tissues.1-5, 7, 8, 12-15, 16-31
The endocannabinoid system (ECS) consists of four main components:
- Anandamide (N-arachidonoylethanolamine/AEA)
- 2-arachidonoylglycerol (2-AG)
- Synthesizing enzymes:
- Diacylglycerol lipase (DGL)
- Degrading enzymes:
- Fatty acid amide hydrolase (FAAH)
- Monoacylglycerol lipase (MGL)
The highest concentration of CB receptors in the body is in the brain, which has more CB receptors than any other receptors. The endocannabinoid system manages process within the brain. These processes are both excitatory and inhibitory and modulate the growth and development of nervous tissue (the hippocampal granule cells) responsible for regulating the release times of endocannabinoids based on the necessities of the brain. Hence the system manages regulation of memory, pain perception, mood, synaptic plasticity, motor learning, appetite, taste, and metabolic functions. The location of cannabinoid receptors binding sites in the brain is related to higher functions, cognitive, movement control and sensory functions of the autonomic nervous system and others.1, 2, 17, 18
Both phytocannabinoids and endocannabinoids bind to any receptors they find in the brain are throughout the body. The anandamide and 2-AG (the endogenous cannabinoids produced by the body) are physiological ligands produced on demand for the CB receptors. They act as reverse transmitters in charge of modulating and balancing signaling and cellular neurotransmission. The endocannabinoid system operates in response to over and under stimulation at synapse or cell surfaces in attempts of modulating homeostasis. The methods that ECS operates include the modulation of the release of neurotransmitters from peripheral and central neurons and secretion of cytokines from macrophages in the spleens marginal zone. The binding ability of phytocannabiniods to CB receptors imitate the mechanisms of homeostasis. The plant-derived cannabinoids have a unique physiological effect on the human body, but generally, have a positive effect on homeostasis modulation.2, 3
CBD is extracted from agricultural hemp; it is non-intoxicating and does not bond with the CB receptors directly. CBD binds allosterically; it interacts with a variety of receptors in the body. These receptors include stress genes like Soat2 and Cyp27a1 that are in charge of sterol metabolism or cholesterol. It also affects mood and pain perception through the 5-HT1A (serotonin) and TRPV1 receptors. Also, CBD was found to increase and preserve anandamide and other lipid concentrations by stopping the production the degrading enzyme. Consequently enlarging the density of endocannabinoid serum circulation, a density which was at risk of being prematurely degraded. It also hastens the binding rate of endocannabinoids at CB receptors.4
The feeling of ‘high’ that people acquaint with experimenting with THC can be alleviated by CBD; when THC binds with CB receptors, a ‘high’ can be induced. CBD will work at this binding site allosterically to reduce the ‘high’.
Clinical Endocannabinoid Dysfunction: Deficiency and Excess
Previous studies have suggested that clinical endocannabinoid deficiency (CECD) is one of the reasons leading to pathological conditions that include a migraine, fibromyalgia, irritable bowel and other symptoms. The study stated that all humans possess an underlying endocannabinoid tone that reflects the levels of endocannabinoids (AEA and 2-AG) their synthesis, metabolism and the density of cannabinoid receptors in the brain. If the endocannabinoid system becomes deficient for any reason, whether acquired or genetic; pathological conditions would develop. Further and more recent review of the study firmly supports the hypothesis and explain the therapeutic benefits of using CBD to rebalance the endocannabinoid system.5 The effectiveness of CBD comes in its ability to increase the serum concentrations of endocannabinoids. However, CECD is one condition, where the overactivity of the endocannabinoid system can also lead to dysfunctions. Both conditions will either be genetic as in the order was inherited, or acquired like an infection or trauma based, or idiopathic autoimmune; the latter is when it is not apparent where the endocannabinoid deficiency stemmed from, genetics or infectious but does result in dysfunctional immunomodulatory effects.
Diseases and disorders fall under one of these categories since all secondary disorders are a result of physiological alterations affiliated with the diagnoses; Irritable bowel syndrome (IBS) is a case in point. IBS is an acquired CECD condition; the syndrome develops either from dietary sources or exposure to prescription drugs. The following progression of multiple sclerosis would then be an idiopathic autoimmune expression of CECD. The physiological homeostasis is locally and remotely affected by deficiencies directly and indirectly; because the endocannabinoid system already expedites coordination and communication between the different cells. Both conditions CECD and endocannabinoid system overactivity is more closely contributing to conditions that include but not limited to cardiovascular diseases, dementia, diabetes, multiple sclerosis, and obesity.5, 32
Obesity one of the most prevalent metabolic diseases, has almost tripled in the past four decades, the World Health Organisation documented in 2016, that almost a third of the world population is overweight, and 13% of all adults were obese. Obesity has become a serious issue that is a significant contributor to the development of cardiovascular diseases (the leading cause of death in 2012), diabetes, musculoskeletal disorders, and cancer. Gastrointestinal inflammation is a subsequence of current modern diets that contain high contents of fat and refined sugar; visceral fat builds up, a fat that is stored deeper inside the body, it is wrapped around vital organs like the liver and kidneys. This accumulation of fat often results in many common diseases through chronic inflammatory and immunologic responses.
Inflammation triggers the response of the immune system, a system which is harmonized to some degree by the endocannabinoid system. Between 70 to 80% of the immune tissue lined with cannabinoid receptors is located either in the digestive or the gastrointestinal tract. This set-up allows the properties of diets to influence the endocannabinoid system directly. A typical modern diet, like the Western diet, has inflammatory properties that would, therefore, activate an acquired CECD or extreme tension of ECS. A response from the immune system to inflammation or injury with trigger a metabolic surge that would inversely lead to more inflammation, microvascular deterioration, and endocannabinoid impairment. Trying to control the resultant damage in the gastrointestinal tract and the chronic inflammation will be challenging especially if exposure to the same diet persists, and an impaired ECS. Metabolic syndromes and obesity consequently will emerge if the same process repeats daily; metabolic syndromes and obesity link directly to severe issues that include insulin resistance and diabetes.4,5, 10-12, 19, 20, 29
An impaired endocannabinoid system due to metabolic syndrome, obesity, insulin resistance or diabetes would also lead to other neurological disorders. The brain inflammatory activity that relates to ECS dysfunction is closely associated with Alzheimer’s and vascular dementia. When the flexibility of the vascular system declines in the presence of increased inflammation, synaptic communications are hindered, and a neurological decline commences. A balanced intake of phytocannabinoids like CBD will lead the restoration of the endocannabinoid purpose and will improve neurological health and function. The neuroprotective benefit of plant-based CBD is supported by research and by US patent 6-630-507.
CBD in Lifestyle Medicine
Internal stability and balance of humans and mammals are dependent on the endocannabinoid system as discussed above; this dependency makes preventative education all-important. Metabolic syndrome a leading causality of global morbidity and mortality is preventable but almost impossible to achieve without a healthy ECS.
Lifestyle changes that are considered essential for maintaining a healthy body and balanced physiologic functioning include nutrition, physical activity, and sound sleep. While all these apply to metabolic syndrome and associated diseases, they are incomplete without addressing the central role of ECS in reaching human homeostasis. Nutritional change on its own will not guarantee weight loss, even if combined with exercise and does reduce weight it will not eliminate visceral fat associated with a metabolic disorder. The endocannabinoid system is imbalanced, and this disproportion is resulting in dysregulations and other physiological processes.
Nitric Oxide (NO) is a primary molecule involved in the regulation and development of inflammation; where under normal circumstances gives an anti-inflammatory effect. However, if circumstances were unusual NO would induce inflammation through overproduction, consequently a cause for the development of metabolic syndrome. Current studies have shown that the endocannabinoid system is an essential player in the regulating the production and release of nitric oxide. This relation correlates with data suggesting the association between tuned NO levels in the body with neurological, cardiovascular and immunological functions. The positive relationship between a tuned level of NO in the body and cannabinoid consumption is a natural consequence, considering the role of ECS in NO regulation.13, 15, 95
The approach of lifestyle medicine unlike conventional, it promotes drug-free, scientific evidence-based treatment, prevention, and reversal of diseases. It includes natural, nourishing diets, physical activity, stress management, alcohol, and nicotine avoidance and healthy relationships. Including phytocannabinoids in the diet plans will promote the balance of the endocannabinoid system and trigger a natural disease reversal and prevention.
Cannabidiol or CBD is a non-intoxicating, non-euphoric but psychoactive/psychotropic (it denotes any chemical that affects a person’s mental state) phytocannabinoid, which has been proven to have beneficial effects on the endocannabinoid system. CBD extracted from Cannabis Sativa has properties that are anti-inflammatory and immune-modulating. The CB1 and CB2 receptors in the human body and CBD have low affinity. However, CBD does have an indirect effect on them; it inhibits action from their agonists by regulating the release of cytokines and neurotransmitters. For all other receptors in the human body, CBD is an agonist.
The phytocannabinoid CBD is not only beneficial for metabolic diseases but in vivo research has shown promising results in the treatment of many conditions that included epilepsy, heart failure, emesis, inflammation, and cancer.7-9 CBD has also proved to be valuable in the prevention and treatment of oxidative neurological and infectious disorders and diseases; due to its antioxidant, antimicrobial and neuroprotective attributes.2, 6-9, 17, 19, 31, 33-94
CBD oil is extracted from legal agricultural hemp and contains less than 0.3% THC; CBD is legal and non-inebriating. CBD has the potential for limitless applications without the impact of unwanted side effects of THC or any of the prescription drugs.
Balancing the endocannabinoid system is essential for the therapeutic benefits and reaching homeostasis. Once the body has a functioning ECS and homeostasis is maintained the body will be able to self-heal. CBD is not the only molecule that is beneficial to the endocannabinoid system, but it is one of the most crucial.
Phytocannabinoids can affect several physiological systems and their related conditions such as:
- the immune system and immunomodulation
- sleep cycles
- traumatic memory elimination
- control of blood pressure and blood sugar
- cancer immunosurveillance
In the following chapters, this book is going to present these systems and their related conditions. It will also illustrate the potential benefit of CBD in their treatment.
- Endocannabinoids: a new class of vasoactive substances, Randall, M.D. et al., Trends in Pharmacological Sciences , Volume 19 , Issue 2 , 55 – 58 (1998) available at https://www.ncbi.nlm.nih.gov/pubmed/9550942
- 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
- Simona Pisanti, Anna Maria Malfitano, Elena Ciaglia, Anna Lamberti, Roberta Ranieri, Gaia Cuomo, Mario Abate, Giorgio Faggiana, Maria Chiara Proto, Donatella Fiore, Chiara Laezza, Maurizio Bifulco, Cannabidiol: State of the art and new challenges for therapeutic applications, Pharmacology & Therapeutics, Volume 175, 2017, Pages 133-150, ISSN 0163-7258, available at http://www.sciencedirect.com/science/article/pii/S0163725817300657
- O’Neill, S. and O’Driscoll, L. (2015), Metabolic syndrome. Obes Rev, 16: 1-12. Available at https://onlinelibrary.wiley.com/doi/abs/10.1111/obr.12229
- Haslam, David W et al. Obesity, The Lancet , Volume 366 , Issue 9492 , 1197 – 1209, available at https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67483-1/fulltext
- Donovan A. Argueta, Nicholas V. DiPatrizio, Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity, Physiology & Behavior, Volume 171, 2017, Pages 32-39, ISSN 0031-9384, available at http://www.sciencedirect.com/science/article/pii/S0031938416309817
- 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
- Gruden, G., Barutta, F., Kunos, G., and Pacher, P. (2016) Role of the endocannabinoid system in diabetes and diabetic complications. Br J Pharmacol, 173: 1116–1127, available at https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.13226
- 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-
- 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
- Novack GD, Cannabinoids for treatment of glaucoma. Current Opinion in Ophthalmology 27:146–150, MAR 2016, available at https://insights.ovid.com/pubmed?pmid=26840343#
- 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
- El-Remessy, Azza B. et al. Neuroprotective Effect of(−)Δ9-Tetrahydrocannabinol and Cannabidiol in N-Methyl-d-Aspartate-Induced Retinal Neurotoxicity. The American Journal of Pathology , Volume 163 , Issue 5 , 1997 – 2008, available at https://ajp.amjpathol.org/article/S0002-9440(10)63558-4/fulltext
- 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
- Tatiana Barichello, Renan A. Ceretta, Jaqueline S. Generoso, Ana Paula Moreira, Lutiana R. Simões, Clarissa M. Comim, João Quevedo, Márcia Carvalho Vilela, Antonio Waldo Zuardi, José A. Crippa, Antônio Lucio Teixeira, Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis, European Journal of Pharmacology, Volume 697, Issues 1–3, 2012, Pages 158-164, ISSN 0014-2999, available at https://doi.org/10.1016/j.ejphar.2012.09.053.
- Hayakawa K, Mishima K, Abe K, Hasebe N, Takamatsu F, Yasuda H, Ikeda T, Inui K, Egashira N, Iwasaki K, Fujiwara M. Cannabidiol prevents infarction via the non-CB1 cannabinoid receptor mechanism. Neuroreport. 2004 Oct 25;15(15):2381-5. Available at https://insights.ovid.com/pubmed?pmid=15640760
- 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
- Chen, J., Simon, P. & Fliri, H. Abnormal Cannabidiols as Agents for Lowering Intraocular Pressure. 2, 1-13 (2013), available at https://patents.google.com/patent/US7618966B2/en
- 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
- Gregory I. Liou, John A. Auchampach, Cecilia J. Hillard, Gu Zhu, Bilal Yousufzai, Salman Mian, Sohail Khan, Yousuf Khalifa; Mediation of Cannabidiol Anti-inflammation in the Retina by Equilibrative Nucleoside Transporter and A2A Adenosine Receptor. Invest. Ophthalmol. Vis. Sci. 2008;49(12):5526-5531. Available at http://iovs.arvojournals.org/article.aspx?articleid=2164704
- Kazuhide Hayakawa, Kenichi Mishima, Masanori Nozako, Ayumi Ogata, Mai Hazekawa, An-Xin Liu, Masayuki Fujioka, Kohji Abe, Nobuyoshi Hasebe, Nobuaki Egashira, Katsunori Iwasaki, Michihiro Fujiwara, Repeated treatment with cannabidiol but not Δ9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance, Neuropharmacology, Volume 52, Issue 4, 2007, Pages 1079-1087, ISSN 0028-3908, available at https://doi.org/10.1016/j.neuropharm.2006.11.005.
- El-Remessy, Azza B. et al. Neuroprotective and Blood-Retinal Barrier-Preserving Effects of Cannabidiol in Experimental Diabetes The American Journal of Pathology, Volume 168, Issue 1, 235 – 244 (2006) available at https://ajp.amjpathol.org/article/S0002-9440(10)62086-X/fulltext
- Fabricio H. Do Monte, Rimenez R. Souza, Rafael M. Bitencourt, Juliana A. Kroon, Reinaldo N. Takahashi, Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors, Behavioural Brain Research, Volume 250, 2013, Pages 23-27, ISSN 0166-4328, available at https://doi.org/10.1016/j.bbr.2013.04.045.
- 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, avaiable 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
- Yu, Y., Chen, H., & Su, S. B. (2015). Neuroinflammatory responses in diabetic retinopathy. Journal of Neuroinflammation, 12, 141. Available at http://doi.org/10.1186/s12974-015-0368-7
- 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
- E Belgrave, B & Bird, Kevin & B Chesher, G & M Jackson, D & E Lubbe, K & A Starmer, G & K Teo, R. (1979). The effect of (-) trans-delta9-tetrahydrocannabinol, alone and in combination with ethanol, on human performance. Psychopharmacology. 62. 53-60. Available at https://www.researchgate.net/publication/23025705_The_effect_of_-_trans-delta9-tetrahydrocannabinol_alone_and_in_combination_with_ethanol_on_human_performance
- 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
- Sharma, J.N., Al-Omran, A. & Parvathy, S.S. Inflammopharmacol (2007) 15: 252. Available at https://doi.org/10.1007/s10787-007-0013-x