Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.

International Cannabis and Cannabinoids Institute Prague Czechia

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Ahmed A., van der Marck M. A., van den Elsen G., Olde Rikkert M. (2015). Cannabinoids in late-onset Alzheimer’s disease. Clin. Pharmacol. Ther. 97, 597–606. 10.1002/cpt.117 PubMed DOI

Aso E., Ferrer I. (2014). Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic. Front. Pharmacol. 5:37. 10.3389/fphar.2014.00037 PubMed DOI PMC

Babson K. A., Sottile J., Morabito D. (2017). Cannabis, cannabinoids, and sleep: a review of the literature. Curr. Psychiatry Rep. 19:23. 10.1007/s11920-017-0775-9 PubMed DOI

Bagdy G., Kecskemeti V., Riba P., Jakus R. (2007). Serotonin and epilepsy. J. Neurochem. 100, 857–873. 10.1111/j.1471-4159.2006.04277.x PubMed DOI

Baker D., Pryce G., Giovannoni G., Thompson A. J. (2003). The therapeutic potential of cannabis. Lancet Neurol. 2, 291–298. 10.1016/s1474-4422(03)00381-8 PubMed DOI

Bergamaschi M. M., Queiroz R. H., Chagas M. H., de Oliveira D. C., De Martinis B. S., Kapczinski F., et al. . (2011). Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology 36, 1219–1226. 10.1038/npp.2011.6 PubMed DOI PMC

Bisogno T., Hanus L., De Petrocellis L., Tchilibon S., Ponde D. E., Brandi I., et al. . (2001). Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br. J. Pharmacol. 134, 845–852. 10.1038/sj.bjp.0704327 PubMed DOI PMC

Bolognini D., Rock E. M., Cluny N. L., Cascio M. G., Limebeer C. L., Duncan M., et al. . (2013). Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br. J. Pharmacol. 168, 1456–1470. 10.1111/bph.12043 PubMed DOI PMC

Bowe W. P., Logan A. C. (2011). Acne vulgaris, probiotics and the gut-brain-skin axis—back to the future? Gut Pathog. 3:1. 10.1186/1757-4749-3-1 PubMed DOI PMC

Brady C. M., DasGupta R., Dalton C., Wiseman O. J., Berkley K. J., Fowler C. J. (2004). An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Mult. Scler. 10, 425–433. 10.1191/1352458504ms1063oa PubMed DOI

Brodie J. S., Di Marzo V., Guy G. W. (2015). Polypharmacology shakes hands with complex aetiopathology. Trends Pharmacol. Sci. 36, 802–821. 10.1016/j.tips.2015.08.010 PubMed DOI

Calame W., Weseler A. R., Viebke C., Flynn C., Siemensma A. D. (2008). Gum arabic establishes prebiotic functionality in healthy human volunteers in a dose-dependent manner. Br. J. Nutr. 100, 1269–1275. 10.1017/S0007114508981447 PubMed DOI

Carroll C. B., Bain P. G., Teare L., Liu X., Joint C., Wroath C., et al. . (2004). Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study. Neurology 63, 1245–1250. 10.1212/01.wnl.0000140288.48796.8e PubMed DOI

Casarejos M. J., Perucho J., Gomez A., Muñoz M. P., Fernandez-Estevez M., Sagredo O., et al. . (2013). Natural cannabinoids improve dopamine neurotransmission and tau and amyloid pathology in a mouse model of tauopathy. J. Alzheimers Dis. 35, 525–539. 10.3233/jad-130050 PubMed DOI

Cascio M. G., Pertwee R. G. (2014). “Known pharmacological actions of nine nonpsychotropic phytocannabinoids,” in Handbook of Cannabis, ed. Pertwee R. G. (Oxford: Oxford Unversity Press; ), 137–156.

Chagas M. H., Eckeli A. L., Zuardi A. W., Pena-Pereira M. A., Sobreira-Neto M. A., Sobreira E. T., et al. . (2014a). Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson’s disease patients: a case series. J. Clin. Pharm. Ther. 39, 564–566. 10.1111/jcpt.12179 PubMed DOI

Chagas M. H., Zuardi A. W., Tumas V., Pena-Pereira M. A., Sobreira E. T., Bergamaschi M. M., et al. . (2014b). Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J. Psychopharmacol. 28, 1088–1098. 10.1177/0269881114550355 PubMed DOI

Cherry J. D., Stein T. D., Tripodis Y., Alvarez V. E., Huber B. R., Au R., et al. . (2017). CCL11 is increased in the CNS in chronic traumatic encephalopathy but not in Alzheimer’s disease. PLoS One 12:e0185541. 10.1371/journal.pone.0185541 PubMed DOI PMC

Clarke G., Cryan J. F., Dinan T. G., Quigley E. M. (2012). Review article: probiotics for the treatment of irritable bowel syndrome—focus on lactic acid bacteria. Aliment. Pharmacol. Ther. 35, 403–413. 10.1111/j.1365-2036.2011.04965.x PubMed DOI

Clendinning J. (1843). Observation on the medicinal properties of Cannabis sativa of India. Med. Chir. Trans. 26, 188–210. 10.1177/095952874302600116 PubMed DOI PMC

Cluny N. L., Keenan C. M., Reimer R. A., Le Foll B., Sharkey K. A. (2015). Prevention of diet-induced obesity effects on body weight and gut microbiota in mice treated chronically with Δ9-tetrahydrocannabinol. PLoS One 10:e0144270. 10.1371/journal.pone.0144270 PubMed DOI PMC

Colle R., de Larminat D., Rotenberg S., Hozer F., Hardy P., Verstuyft C., et al. . (2017a). Pioglitazone could induce remission in major depression: a meta-analysis. Neuropsychiatr. Dis. Treat. 13, 9–16. 10.2147/ndt.s121149 PubMed DOI PMC

Colle R., de Larminat D., Rotenberg S., Hozer F., Hardy P., Verstuyft C., et al. . (2017b). PPAR-γ agonists for the treatment of major depression: a review. Pharmacopsychiatry 50, 49–55. 10.1055/s-0042-120120 PubMed DOI

Cordain L., Lindeberg S., Hurtado M., Hill K., Eaton S. B., Brand-Miller J. (2002). Acne vulgaris: a disease of Western civilization. Arch. Dermatol. 138, 1584–1590. 10.1001/archderm.138.12.1584 PubMed DOI

Devinsky O., Cross J. H., Laux L., Marsh E., Miller I., Nabbout R., et al. . (2017). Trial of cannabidiol for drug-resistant seizures in the dravet syndrome. N. Engl. J. Med. 376, 2011–2020. 10.1056/NEJMoa1611618 PubMed DOI

Devinsky O., Marsh E., Friedman D., Thiele E., Laux L., Sullivan J., et al. . (2016). Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 15, 270–278. 10.1016/s1474-4422(15)00379-8 PubMed DOI

Devinsky O., Patel A. D., Thiele E. A., Wong M. H., Appleton R., Harden C. L., et al. . (2018). Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology 90, e1204–e1211. 10.1212/wnl.0000000000005254 PubMed DOI PMC

Donovan M. (1845). On the physical and medicinal qualities of Indian hemp (Cannabis indica); with observations on the best mode of administration and cases illustrative of its powers. Dubl. J. Med. Sci. 26, 368–402. 10.1007/bf02971741 DOI

Dumitru C. A., Sandalcioglu I. E., Karsak M. (2018). Cannabinoids in glioblastoma therapy: new applications for old drugs. Front. Mol. Neurosci. 11:159. 10.3389/fnmol.2018.00159 PubMed DOI PMC

Elrod H. A., Sun S. Y. (2008). PPARγ and apoptosis in cancer. PPAR Res. 2008:704165. 10.1155/2008/704165 PubMed DOI PMC

Emery D. C., Shoemark D. K., Batstone T. E., Waterfall C. M., Coghill J. A., Cerajewska T. L., et al. . (2017). 16S rRNA next generation sequencing analysis shows bacteria in Alzheimer’s post-mortem brain. Front. Aging Neurosci. 9:195. 10.3389/fnagi.2017.00195 PubMed DOI PMC

Esposito G., De Filippis D., Maiuri M. C., De Stefano D., Carnuccio R., Iuvone T. (2006). Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in β-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-κB involvement. Neurosci. Lett. 399, 91–95. 10.1016/j.neulet.2006.01.047 PubMed DOI

Esposito G., Scuderi C., Valenza M., Togna G. I., Latina V., De Filippis D., et al. . (2011). Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One 6:e28668. 10.1371/journal.pone.0028668 PubMed DOI PMC

Eubanks L. M., Rogers C. J., Beuscher A. E., IV., Koob G. F., Olson A. J., Dickerson T. J., et al. . (2006). A molecular link between the active component of marijuana and Alzheimer’s disease pathology. Mol. Pharm. 3, 773–777. 10.1021/mp060066m PubMed DOI PMC

Fallon S., Enig M. C. (1999). Nourishing Traditions: The Cookbook That Challenges Politically Correct Nutrtition and the Diet Dictocrats. Washington, DC: New Trends Publishing.

Fife T. D., Moawad H., Moschonas C., Shepard K., Hammond N. (2015). Clinical perspectives on medical marijuana (cannabis) for neurologic disorders. Neurol. Clin. Pract. 5, 344–351. 10.1212/cpj.0000000000000162 PubMed DOI PMC

Finseth T. A., Hedeman J. L., Brown R. P., II., Johnson K. I., Binder M. S., Kluger B. M. (2015). Self-reported efficacy of cannabis and other complementary medicine modalities by Parkinson’s disease patients in colorado. Evid. Based Complement. Alternat. Med. 2015:874849. 10.1155/2015/874849 PubMed DOI PMC

Foroughi M., Hendson G., Sargent M. A., Steinbok P. (2011). Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas—possible role of Cannabis inhalation. Childs. Nerv. Syst. 27, 671–679. 10.1007/s00381-011-1410-4 PubMed DOI

Gehring S., Tapia-Pérez J. H., Kirches E., Firsching R., Keilhoff G., Schneider T., et al. . (2011). Cytotoxic effects of statins and thiazolidinediones on meningioma cells. J. Neurooncol. 102, 383–393. 10.1007/s11060-010-0351-1 PubMed DOI

Gottschling S. (2011). Cannbinoide bei kindern. gute erfahrungen bei schmerzen, spastik und in der onkologie. Ange. Schmerzth. Palliat. 4, 55–57. 10.1007/bf03359593 DOI

Gowers W. R. (1888). A Manual of Diseases of the Nervous System. Philadelphia, PA: P. Blakiston Son & Co.

Guzmán M., Duarte M. J., Blázquez C., Ravina J., Rosa M. C., Galve-Roperh I., et al. . (2006). A pilot clinical study of Δ9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br. J. Cancer 95, 197–203. 10.1038/sj.bjc.6603236 PubMed DOI PMC

Hampson A. J., Grimaldi M., Axelrod J., Wink D. (1998). Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc. Natl. Acad. Sci. U S A 95, 8268–8273. 10.1073/pnas.95.14.8268 PubMed DOI PMC

He M., Shi B. (2017). Gut microbiota as a potential target of metabolic syndrome: the role of probiotics and prebiotics. Cell Biosci. 7:54. 10.1186/s13578-017-0183-1 PubMed DOI PMC

Hergenrather J. (2017). Cannabis and Dementia. Columbus, OH: Cannabis Expertise.

Herrera Moro Chao D., Argmann C., Van Eijk M., Boot R. G., Ottenhoff R., Van Roomen C., et al. . (2016). Impact of obesity on taste receptor expression in extra-oral tissues: emphasis on hypothalamus and brainstem. Sci. Rep. 6:29094. 10.1038/srep29094 PubMed DOI PMC

Hill M. N., Bierer L. M., Makotkine I., Golier J. A., Galea S., McEwen B. S., et al. . (2013). Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks. Psychoneuroendocrinology 38, 2952–2961. 10.1016/j.psyneuen.2013.08.004 PubMed DOI PMC

Iuvone T., Esposito G., Esposito R., Santamaria R., Di Rosa M., Izzo A. A. (2004). Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on β-amyloid-induced toxicity in PC12 cells. J. Neurochem. 89, 134–141. 10.1111/j.1471-4159.2003.02327.x PubMed DOI

Johnson J. R., Burnell-Nugent M., Lossignol D., Ganae-Motan E. D., Potts R., Fallon M. T. (2010). Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J. Pain Symptom Manage. 39, 167–179. 10.1016/j.jpainsymman.2009.06.008 PubMed DOI

Jones N. A., Hill A. J., Smith I., Bevan S. A., Williams C. M., Whalley B. J., et al. . (2010). Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J. Pharmacol. Exp. Ther. 332, 569–577. 10.1124/jpet.109.159145 PubMed DOI PMC

Kales H. C., Valenstein M., Kim H. M., McCarthy J. F., Ganoczy D., Cunningham F., et al. . (2007). Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications. Am. J. Psychiatry 164, 1568–1576; quiz 1623. 10.1176/appi.ajp.2007.06101710 PubMed DOI

Karler R., Turkanis S. A. (1979). “Cannabis and epilepsy,” in Marihuana Biological Effects: Analysis, Metabolism, Cellular Responses, Reproduction and Brain, eds Nahas G. G., Paton W. D. M. (Oxford, UK: Pergamon Press; ), 619–641.

Kavia R., De Ridder D., Constantinescu C., Stott C., Fowler C. (2010). Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult. Scler. 16, 1349–1359. 10.1177/1352458510378020 PubMed DOI

Keshavarzian A., Green S. J., Engen P. A., Voigt R. M., Naqib A., Forsyth C. B., et al. . (2015). Colonic bacterial composition in Parkinson’s disease. Mov. Disord. 30, 1351–1360. 10.1002/mds.26307 PubMed DOI

Kim S. S., Baik J. S., Oh T. H., Yoon W. J., Lee N. H., Hyun C. G. (2008). Biological activities of Korean Citrus obovoides and Citrus natsudaidai essential oils against acne-inducing bacteria. Biosci. Biotechnol. Biochem. 72, 2507–2513. 10.1271/bbb.70388 PubMed DOI

Latorre J. G., Schmidt E. B. (2015). Cannabis, cannabinoids, and cerebral metabolism: potential applications in stroke and disorders of the central nervous system. Curr. Cardiol. Rep. 17:627. 10.1007/s11886-015-0627-3 PubMed DOI

Lei P., Ayton S., Finkelstein D. I., Adlard P. A., Masters C. L., Bush A. I. (2010). Tau protein: relevance to Parkinson’s disease. Int. J. Biochem. Cell Biol. 42, 1775–1778. 10.1016/j.biocel.2010.07.016 PubMed DOI

Leweke F. M., Piomelli D., Pahlisch F., Muhl D., Gerth C. W., Hoyer C., et al. . (2012). Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl. Psychiatry 2:e94. 10.1038/tp.2012.15 PubMed DOI PMC

Lewis M. A., Russo E. B., Smith K. M. (2018). Pharmacological foundations of cannabis chemovars. Planta Med. 84, 225–233. 10.1055/s-0043-122240 PubMed DOI

Ligresti A., Moriello A. S., Starowicz K., Matias I., Pisanti S., De Petrocellis L., et al. . (2006). Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J. Pharmacol. Exp. Ther. 318, 1375–1387. 10.1124/jpet.106.105247 PubMed DOI

Lorenz R. (2004). On the application of cannabis in paediatrics and epileptology. Neuro Endocrinol. Lett. 25, 40–44. PubMed

Lotan I., Treves T. A., Roditi Y., Djaldetti R. (2014). Cannabis (medical marijuana) treatment for motor and non-motor symptoms of Parkinson disease: an open-label observational study. Clin. Neuropharmacol. 37, 41–44. 10.1097/wnf.0000000000000016 PubMed DOI

Maa E., Figi P. (2014). The case for medical marijuana in epilepsy. Epilepsia 55, 783–786. 10.1111/epi.12610 PubMed DOI

Maas A. I., Murray G., Henney H., III., Kassem N., Legrand V., Mangelus M., et al. . (2006). Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 5, 38–45. 10.1016/s1474-4422(05)70253-2 PubMed DOI

MacCallum C. A., Russo E. B. (2018). Practical considerations in medical cannabis administration and dosing. Eur. J. Intern. Med. 49, 12–19. 10.1016/j.ejim.2018.01.004 PubMed DOI

Maccarrone M., Maldonado R., Casas M., Henze T., Centonze D. (2017). Cannabinoids therapeutic use: what is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others? Expert Rev. Clin. Pharmacol. 10, 443–455. 10.1080/17512433.2017.1292849 PubMed DOI

Massi P., Vaccani A., Ceruti S., Colombo A., Abbracchio M. P., Parolaro D. (2004). Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. J. Pharmacol. Exp. Ther. 308, 838–845. 10.1124/jpet.103.061002 PubMed DOI

Mayeux R., Stern Y. (2012). Epidemiology of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2:a006239. 10.1101/cshperspect.a006239 PubMed DOI PMC

McGuire P., Robson P., Cubala W. J., Vasile D., Morrison P. D., Barron R., et al. . (2018). Cannabidiol (CBD) as an adjunctive therapy in schizophrenia: a multicenter randomized controlled trial. Am. J. Psychiatry 175, 225–231. 10.1176/appi.ajp.2017.17030325 PubMed DOI

McPartland J. M., MacDonald C., Young M., Grant P. S., Furkert D. P., Glass M. (2017). Affinity and efficacy studies of tetrahydrocannabinolic acid A at cannabinoid receptor types one and two. Cannabis Cannabinoid Res. 2, 87–95. 10.1089/can.2016.0032 PubMed DOI PMC

Merritt J. C., Crawford W. J., Alexander P. C., Anduze A. L., Gelbart S. S. (1980). Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 87, 222–228. 10.1016/s0161-6420(80)35258-5 PubMed DOI

Mez J., Daneshvar D. H., Kiernan P. T., Abdolmohammadi B., Alvarez V. E., Huber B. R., et al. . (2017). Clinicopathological evaluation of chronic traumatic encephalopathy in players of american football. JAMA 318, 360–370. 10.1001/jama.2017.8334 PubMed DOI PMC

Mitchell S. W. (1874). Headaches, from heat-stroke, from fevers, after meningitis, from over use of brain, from eye strain. Med. Surg. Rep. 31, 67–70.

Müller-Vahl K. R., Schneider U., Emrich H. M. (2002). Combined treatment of Tourette syndrome with Δ-9-THC and dopamine receptor agonists. J. Cannab. Thera. 2, 145–154. 10.1300/j175v02n03_10 DOI

Müller-Vahl K. R., Schneider U., Prevedel H., Theloe K., Kolbe H., Daldrup T., et al. . (2003). Δ9-tetrahydrocannabinol (THC) is effective in the treatment of tics in tourette syndrome: a 6-week randomized trial. J. Clin. Psychiatry 64, 459–465. 10.4088/jcp.v64n0417 PubMed DOI

Munson A. E., Harris L. S., Friedman M. A., Dewey W. L., Carchman R. A. (1975). Antineoplastic activity of cannabinoids. J. Natl. Cancer Inst. 55, 597–602. PubMed

Musso G., Gambino R., Cassader M. (2010). Gut microbiota as a regulator of energy homeostasis and ectopic fat deposition: mechanisms and implications for metabolic disorders. Curr. Opin. Lipidol. 21, 76–83. 10.1097/mol.0b013e3283347ebb PubMed DOI

Nadal X., Del Río C., Casano S., Palomares B., Ferreiro-Vera C., Navarrete C., et al. . (2017). Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Br. J. Pharmacol. 174, 4263–4276. 10.1111/bph.14019 PubMed DOI PMC

National Academies of Sciences Engineering and Medicine (U.S.). Committee on the Health Effects of Marijuana: An Evidence Review and Research Agenda (2017). The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. PubMed

Novotna A., Mares J., Ratcliffe S., Novakova I., Vachova M., Zapletalova O., et al. . (2011). A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur. J. Neurol. 18, 1122–1131. 10.1111/j.1468-1331.2010.03328.x PubMed DOI

Nozaki C., Markert A., Zimmer A. (2015). Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice. Eur. Neuropsychopharmacol. 25, 1388–1396. 10.1016/j.euroneuro.2015.04.001 PubMed DOI

Nurmikko T. J., Serpell M. G., Hoggart B., Toomey P. J., Morlion B. J., Haines D. (2007). Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain 133, 210–220. 10.1016/j.pain.2007.08.028 PubMed DOI

Oby E., Janigro D. (2006). The blood-brain barrier and epilepsy. Epilepsia 47, 1761–1774. 10.1111/j.1528-1167.2006.00817.x PubMed DOI

Oláh A., Tóth B. I., Borbirò I., Sugawara K., Szöllõsi A. G., Czifra G., et al. . (2014). Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. J. Clin. Invest. 124, 3713–3724. 10.1172/jci64628 PubMed DOI PMC

Omalu B., Small G. W., Bailes J., Ercoli L. M., Merrill D. A., Wong K. P., et al. . (2018). Postmortem autopsy-confirmation of antemortem [F-18]FDDNP-PET scans in a football player with chronic traumatic encephalopathy. Neurosurgery 82, 237–246. 10.1093/neuros/nyx536 PubMed DOI PMC

O’Shaughnessy W. B. (1838–1840). On the preparations of the Indian hemp, or gunjah (Cannabis indica); Their effects on the animal system in health and their utility in the treatment of tetanus and other convulsive diseases. Trans. Med. Phys. Soc. Bengal 71–102, 421–461. PubMed PMC

Osler W., McCrae T. (1915). The Principles and Practice of Medicine. New York, NY London: Appleton and Company.

Pacher P., Steffens S., Haskó G., Schindler T. H., Kunos G. (2018). Cardiovascular effects of marijuana and synthetic cannabinoids: the good, the bad, and the ugly. Nat. Rev. Cardiol. 15, 151–166. 10.1038/nrcardio.2017.130 PubMed DOI

Pamplona F. A., da Silva L. R., Coan A. C. (2018). Potential clinical benefits of CBD-rich Cannabis extracts over purified CBD in treatment-resistant epilepsy: Observational data meta-analysis. Front. Neurol. 9:759. 10.3389/fneur.2018.00759 PubMed DOI PMC

Perlmutter F., Loberg K. (2015). Brain Maker. The Power of Gut Microbes to Heal and Protect Your Brain—For Life. New York, NY: Little, Brown and Co.

Pertwee R. G., Cascio M. G. (2014). “Known pharmacological actions of Δ-9-tetrahydrocannabinol and of four other chemical constituents that activate cannabinoid receptors,” in Handbook of Cannabis, ed. Pertwee R. G. (Oxford: Oxford University Press; ), 115–136.

Pisani A., Fezza F., Galati S., Battista N., Napolitano S., Finazzi-Agro A., et al. . (2005). High endogenous cannabinoid levels in the cerebrospinal fluid of untreated Parkinson’s disease patients. Ann. Neurol. 57, 777–779. 10.1002/ana.20462 PubMed DOI

Porter B. E., Jacobson C. (2013). Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. 29, 574–577. 10.1016/j.yebeh.2013.08.037 PubMed DOI PMC

Press C. A., Knupp K. G., Chapman K. E. (2015). Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy. Epilepsy Behav. 45, 49–52. 10.1016/j.yebeh.2015.02.043 PubMed DOI

Raichlen D. A., Foster A. D., Gerdeman G. L., Seillier A., Giuffrida A. (2012). Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the ‘runner’s high’. J. Exp. Biol. 215, 1331–1336. 10.1242/jeb.063677 PubMed DOI

Raman A., Weir U., Bloomfield S. F. (1995). Antimicrobial effects of tea-tree oil and its major components on Staphylococcus aureus, Staph. epidermidis and Propionibacterium acnes. Lett. Appl. Microbiol. 21, 242–245. 10.1111/j.1472-765x.1995.tb01051.x PubMed DOI

Rekand T. (2014). THC:CBD spray and MS spasticity symptoms: data from latest studies. Eur. Neurol. 71, 4–9. 10.1159/000357742 PubMed DOI

Reymond E. A. E. E. (1976). From the Contents of the Libraries of the Suchos Temple in the Fayyum, Part I, A Medical Book From Crocodilopolis. Papyrus Vindobonensis D. 6257. Vienna, Austria: Österreichische Nationalbibliothek.

Rhyne D. N., Anderson S. L., Gedde M., Borgelt L. M. (2016). Effects of medical marijuana on migraine headache frequency in an adult population. Pharmacotherapy 36, 505–510. 10.1002/phar.1673 PubMed DOI

Rog D. J., Nurmiko T., Friede T., Young C. (2005). Randomized controlled trial of cannabis based medicine in central neuropathic pain due to multiple sclerosis. Neurology 65, 812–819. 10.1212/01.wnl.0000176753.45410.8b PubMed DOI

Rousseaux C., Thuru X., Gelot A., Barnich N., Neut C., Dubuquoy L., et al. . (2007). Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat. Med. 13, 35–37. 10.1038/nm1521 PubMed DOI

Rudroff T., Honce J. M. (2017). Cannabis and multiple sclerosis-the way forward. Front. Neurol. 8:299. 10.3389/fneur.2017.00299 PubMed DOI PMC

Russo E. B. (2001). Hemp for headache: an in-depth historical and scientific review of cannabis in migraine treatment. J. Canna. Thera. 1, 21–92. 10.1300/j175v01n02_04 DOI

Russo E. B. (2004). Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol. Lett. 25, 31–39. PubMed

Russo E. B. (2007). History of cannabis and its preparations in saga, science and sobriquet. Chem. Biodivers 4, 2624–2648. 10.1002/cbdv.200790144 PubMed DOI

Russo E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br. J. Pharmacol. 163, 1344–1364. 10.1111/j.1476-5381.2011.01238.x PubMed DOI PMC

Russo E. B. (2015). Synthetic and natural cannabinoids: the cardiovascular risk. Br. J. Cardiol. 22, 7–9.

Russo E. B. (2016a). Beyond cannabis: plants and the endocannabinoid system. Trends Pharmacol. Sci. 37, 594–605. 10.1016/j.tips.2016.04.005 PubMed DOI

Russo E. B. (2016b). Clinical endocannabinoid deficiency reconsidered: current research supports the theory in migraine, fibromyalgia, irritable bowel, and other treatment-resistant syndromes. Cannabis Cannabinoid Res. 1, 154–165. 10.1089/can.2016.0009 PubMed DOI PMC

Russo E. B. (2017a). Cannabis and epilepsy: an ancient treatment returns to the fore. Epilepsy Behav. 70, 292–297. 10.1016/j.yebeh.2016.09.040 PubMed DOI

Russo E. B. (2017b). “History of cannabis as medicine: nineteenth century irish physicians and correlations of their observations to modern research,” in Cannabis Sativa L.: Botany and Biotechnology, eds Chanda S., Lata H., Elsohly M. (Switzerland: Springer International Publishing; ), 63–78.

Russo E. B., Burnett A., Hall B., Parker K. K. (2005). Agonistic properties of cannabidiol at 5-HT-1a receptors. Neurochem. Res. 30, 1037–1043. 10.1007/s11064-005-6978-1 PubMed DOI

Russo E. B., Guy G. W., Robson P. J. (2007). Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem. Biodivers 4, 1729–1743. 10.1002/cbdv.200790150 PubMed DOI

Russo E. B., Hohmann A. G. (2013). “Role of cannabinoids in pain management,” in Comprehensive Treatment of Chronic Pain by Medical, Interventional and Behavioral Approaches, eds Deer T., Gordin V. (New York, NY: Springer; ), 181–197.

Russo E. B., Marcu J. (2017). Cannabis pharmacology: the usual suspects and a few promising leads. Adv. Pharmacol. 80, 67–134. 10.1016/bs.apha.2017.03.004 PubMed DOI

Russo E. B., Mead A. P., Sulak D. (2015). Current status and future of cannabis research. Clin. Res. 58–63. 10.14524/CR-15-0004 DOI

Sampson T. R., Debelius J. W., Thron T., Janssen S., Shastri G. G., Ilhan Z. E., et al. . (2016). Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469.e12–1480.e12. 10.1016/j.cell.2016.11.018 PubMed DOI PMC

Sánchez C., Galve-Roperh I., Canova C., Brachet P., Guzmán M. (1998). Δ9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett. 436, 6–10. 10.1016/s0014-5793(98)01085-0 PubMed DOI

Sarchielli P., Pini L. A., Coppola F., Rossi C., Baldi A., Mancini M. L., et al. . (2007). Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology 32, 1384–1390. 10.1038/sj.npp.1301320 PubMed DOI

Schenkman M., Moore C. G., Kohrt W. M., Hall D. A., Delitto A., Comella C. L., et al. . (2018). Effect of high-intensity treadmill exercise on motor symptoms in patients with de novo Parkinson disease: a phase 2 randomized clinical trial. JAMA Neurol. 75, 219–226. 10.1001/jamaneurol.2017.3517 PubMed DOI PMC

Seguin E. (1877). Contribution to the therapeutics of migraine. Med. Rec. 12, 774–776.

Serpell M., Ratcliffe S., Hovorka J., Schofield M., Taylor L., Lauder H., et al. . (2014). A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur. J. Pain 18, 999–1012. 10.1002/j.1532-2149.2013.00445.x PubMed DOI

Shen Y., Lu Y., Yu F., Zhu C., Wang H., Wang J. (2016). Peroxisome proliferator-activated receptor-γ and its ligands in the treatment of tumors in the nervous system. Curr. Stem Cell Res. Ther. 11, 208–215. 10.2174/1574888X10666150728122034 PubMed DOI

Slavin J. (2013). Fiber and prebiotics: mechanisms and health benefits. Nutrients 5, 1417–1435. 10.3390/nu5041417 PubMed DOI PMC

Soni D., Smoum R., Breuer A., Mechoulam R., Steinberg D. (2015). Effect of the synthetic cannabinoid HU-210 on quorum sensing and on the production of quorum sensing-mediated virulence factors by Vibrio harveyi. BMC Microbiol. 15:159. 10.1186/s12866-015-0499-0 PubMed DOI PMC

Subramenium G. A., Vijayakumar K., Pandian S. K. (2015). Limonene inhibits streptococcal biofilm formation by targeting surface-associated virulence factors. J. Med. Microbiol. 64, 879–890. 10.1099/jmm.0.000105 PubMed DOI

Sulak D., Saneto R., Goldstein B. (2017). The current status of artisanal cannabis for the treatment of epilepsy in the United States. Epilepsy Behav. 70, 328–333. 10.1016/j.yebeh.2016.12.032 PubMed DOI

Sun H., Huang Y., Yu X., Li Y., Yang J., Li R., et al. . (2008). Peroxisome proliferator-activated receptor γ agonist, rosiglitazone, suppresses CD40 expression and attenuates inflammatory responses after lithium pilocarpine-induced status epilepticus in rats. Int. J. Dev. Neurosci. 26, 505–515. 10.1016/j.ijdevneu.2008.01.009 PubMed DOI

Tepper B. J., Banni S., Melis M., Crnjar R., Tomassini Barbarossa I. (2014). Genetic sensitivity to the bitter taste of 6-n-propylthiouracil (PROP) and its association with physiological mechanisms controlling body mass index (BMI). Nutrients 6, 3363–3381. 10.3390/nu6093363 PubMed DOI PMC

Thiele E. A., Marsh E. D., French J. A., Mazurkiewicz-Beldzinska M., Benbadis S. R., Joshi C., et al. . (2018). Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 391, 1085–1096. 10.1016/S0140-6736(18)30136-3 PubMed DOI

Torres S., Lorente M., Rodríguez-Fornés F., Hernández-Tiedra S., Salazar M., García-Taboada E., et al. . (2011). A combined preclinical therapy of cannabinoids and temozolomide against glioma. Mol. Cancer Ther. 10, 90–103. 10.1158/1535-7163.mct-10-0688 PubMed DOI

van den Elsen G. A., Ahmed A. I., Verkes R. J., Kramers C., Feuth T., Rosenberg P. B., et al. . (2015). Tetrahydrocannabinol for neuropsychiatric symptoms in dementia: a randomized controlled trial. Neurology 84, 2338–2346. 10.1212/WNL.0000000000001675 PubMed DOI PMC

Venderová K., Ruzicka E., Vorísek V., Visnovský P. (2004). Survey on cannabis use in Parkinson’s disease: subjective improvement of motor symptoms. Mov. Disord. 19, 1102–1106. 10.1002/mds.20111 PubMed DOI

Volicer L., Stelly M., Morris J., McLaughlin J., Volicer B. J. (1997). Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease. Int. J. Geriatr. Psychiatry 12, 913–919. 10.1002/(sici)1099-1166(199709)12:9<913::aid-gps663>3.3.co;2-4 PubMed DOI

Wallace M. J., Blair R. E., Falenski K. W., Martin B. R., DeLorenzo R. J. (2003). The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy. J. Pharmacol. Exp. Ther. 307, 129–137. 10.1124/jpet.103.051920 PubMed DOI

Walther S., Mahlberg R., Eichmann U., Kunz D. (2006). Δ-9-tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology 185, 524–528. 10.1007/s00213-006-0343-1 PubMed DOI

Zhang L., Papadopoulos P., Hamel E. (2013). Endothelial TRPV4 channels mediate dilation of cerebral arteries: impairment and recovery in cerebrovascular pathologies related to Alzheimer’s disease. Br. J. Pharmacol. 170, 661–670. 10.1111/bph.12315 PubMed DOI PMC

Zuardi A. W., Crippa J. A., Hallak J. E., Pinto J. P., Chagas M. H., Rodrigues G. G., et al. . (2009). Cannabidiol for the treatment of psychosis in Parkinson’s disease. J. Psychopharmacol. 23, 979–983. 10.1177/0269881108096519 PubMed DOI