The history of cannabis as a medicine
Medicinal properties of cannabis described in the world’s oldest pharmacopoeia, Shennong bencaojing (神农本草经）
What is Cannabis?
The secondary metabolites profiled in cannabis can fall into four major categories:
Cannabinoids: Cannabinoids are naturally occurring compounds found in cannabis. These include the psychoactive ∆9-THC  and non-psychoactive CBD . Up to now, more than 100 cannabinoids have been identified in cannabis [11–17]. Cannabinoids have pain-relieving, anti-inflammatory, antioxidant and neuroprotective properties [18–20].
Terpenes: Terpenes are the compounds responsible for the smell of cannabis. Each strain has its own unique combination of terpenes which give it distinct aroma and flavour. Up to now, more than 120 terpenes have been identified in cannabis [11–17]. Terpenes also have pain-relieving, anti-inflammatory, antioxidant and neuroprotective properties [21–23].
Flavonoids: Flavonoids are a group of plant chemicals that are the essential pigments responsible for their diverse colouration. Flavonoids share a wide range of biological effects with cannabinoids and terpenes that include anti-inflammatory, anti-cancer, and neuroprotective properties .
Sterols: Plant sterols are substance found in plants that resemble cholesterol. There is evidence that shows plant sterols may lower cholesterol in certain cases .
Figure. Microscopic view of glandular (upper two) and non-glandular (down two) trichomes (Sourced from Recommended methods for the identification and analysis of cannabis and cannabis products, United Nations Office on Drugs and Crime, New York, 2009 )
What is the entourage effect?
Cannabis is made up of a number of compounds that act together to create something called the “entourage effect” or “synergistic effect” [25–27]. Studies have shown that extracts of the entire plant has better medicinal effects than pure CBD or THC alone [26, 28]. However, the molecular mechanisms behind this effect are still under investigation.
What’s a landrace?
A landrace in cannabis terms refers to a so called “pure” strain, which can be traced back to its country of origin. In other terms, a strain that has not been crossbred.
What are trichomes?
Trichomes are the little hairy outgrowths on the buds and leaves of cannabis. These little appendages contain the majority of the cannabis’ cannabinoids and terpenes. There are two types and distributions of cannabis trichomes: a glandular type that produces cannabinoids and a non-glandular type that does not.
Botanical C. sativa and C. indica
Whether Cannabis genus has one species or multiple species is still a debate. In 1753, Linnaeus first described C. sativa L. as a single species in Species Plantarum , with herbarium specimens covered with sparse trichomes and resembling a northern European fiber-type landrace . A second species or a subspecies collected in India, C. indica Lam., was proposed by de Lamarck in 1785, with dense trichomes, narrower leaflets, and psychoactive effects .
In 2005, Hillig systematically classified cannabis from all around the world into two species and seven putative biotypes using genetic, chemotypic, and phenotypic variations . The sativa gene pool included hemp landraces from Europe, Asia Minor, and Central Asia, feral landraces from eastern Europe, and ruderal populations from eastern Europe. The indica gene pool included two drug types, hemp landraces from southern and eastern Asia, and feral landraces from India and Nepal. These two drug types included narrow-leaflet drugs (NLD) of Indian heritage (including varieties of the Indian subcontinent, Africa, and other drug producing regions) and wide-leaflet drug (WLD) or broad-leaflet drug (BLD) from Afghanistan and Pakistan. Almost all modern varieties with high THC concentrations are hybrids of these two landraces.
Interestingly, chemical analysis found that C. sativa hemp landraces from Europe produced the highest CBD content among all seven biotypes while being almost devoid of THC. C. indica hemp landraces from southern and eastern Asia (China, Korea, etc.) had relatively high levels of CBD as well as THC.
Figure. Map showing the countries of origin of accessions assigned to the indica and sativa gene pools. The arrows suggest human-vectored dispersal from the presumed origin of Cannabis in Central Asia. (Picture modified from Hillig (2005) A systematic investigation of Cannabis ）
Figure. Present-day ranges of Cannabis. (Modified from Hillig (2005) A systematic investigation of Cannabis , and Clarke and Merlin MD (2013) Cannabis: Evolution and Ethnobotany ）
Modern cannabis strains: vernacular “Sativa” and “Indica”
Since the 1980s, almost all cannabis varieties are hybrids between NLD and WLD, bred in the pursuit of high THC levels for recreational purposes. These hybrids are called sinsemilla (seedless) strains as they are grown using clones and cuttings of female plants and no seeds are produced. There are also CBD dominant strains and intermediate strains (where THC content is roughly equal to CBD content) bred for medical purposes in recent years.
Cannabis users widely use the vernacular terminology “Sativa” to describe THC dominant varieties with narrow-leaflets (NLD) and “Indica” to describe THC dominant varieties with wide or broad leaflets (WLD/BLD). However, all drug strains are descendants of C. indica landraces, so this nomenclature has no scientific basis. This misnomer originated from an illustration done in the 1980s by Anderson , which deviated Linnaeus’s and de Lamarck’s concepts. This illustration incorrectly named plants with broad leaflets from Afghanistan as “Indica” and plants with narrow leaflets from Indica as “Sativa”. Furthermore, these categories lose even more credibility since they were used arbitrarily for labelling strains during the extensive underground hybridization of cannabis in the past 40 years .
McPartland (2017) Cannabis sativa and Cannabis indica versus “Sativa” and “Indica”
Cannabis chemotypes(chemical phenotypes)
Cannabis and hemp forindustrial applications
Approved by FDA?
Treatment of severe nausea and vomiting associated with cancer chemotherapy, and for AIDS-related anorexia associated with weight loss
Treatment of severe nausea and vomiting associated with cancer chemotherapy
Whole-plant extract of two different strains of Cannabis sativa
Adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis in adults.
Pure CBD liquid formulation (at least 98% (w/w) CBD)
Treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome in patients 2 years of age and older.
Therapeutic effects of cannabis and cannabinoids [41,42]
Compunds and their Therapeutic Uses
Nausea and vomiting
Cesamet®(Nabilone), Marinol®(Dronabinol), THC
Wasting syndrome and loss of appetite in AIDS and cancer patients, and Anorexia nervosa
Cesamet®(Nabilone), Marinol®(Dronabinol), THC, smoked cannabis
Spasticity associated with multiple sclerosis or spinal cord injury
Cannabis extract (THC and CBD), oral THC, Sativex® (Nabiximols)
Cannabis (THC and CBD), CBD
Acute pain: experimentally induced acute pain
Smoked cannabis (THC), oral THC and cannabis extract, Cesamet®(Nabilone)
THC, Cesamet®(Nabilone), an oral cannabis extract containing a 2:1 ratio of THC to CBD
Chronic pain: Neuropathic pain or chronic non-cancer pain
Smoked cannabis, oromucosal cannabis sprays, oral cannabinoids (Cesamet®(Nabilone)), Sativex® (Nabiximols)
Chronic pain: cancer pain
Marinol®(Dronabinol), Sativex® (Nabiximols), THC, CBD
Chronic pain: Headache and migraine
Smoked cannabis, Marinol®(Dronabinol)
Arthritides and musculoskeletal disorders: Osteoarthritis
Agonist (ACEA) for endocannabinoid receptors
Arthritides and musculoskeletal disorders: Rheumatoid arthritis
Arthritides and musculoskeletal disorders: Fibromyalgia
Smoked or orally ingested cannabis, Marinol®(Dronabinol), Cesamet®(Nabilone)
Amyotrophic lateral sclerosis (ALS)
Movement disorders: Dystonia
Movement disorders: Huntington‘s disease
Movement disorders: Parkinson‘s disease
CBD, smoked cannabis
Movement disorders: Tourette‘s syndrome
THC, CBD, CBG
Traumatic brain injury (TBI)/intracranial hemorrhage (ICH)
THC, cannabis use
Psychiatric disorders: Anxiety
Marinol®(Dronabinol), Cesamet®(Nabilone), Sativex® (Nabiximols), CBD
Psychiatric disorders: Depression
Marinol®(Dronabinol), Cesamet®(Nabilone), Sativex® (Nabiximols)
Psychiatric disorders: Sleep disorders
Marinol®(Dronabinol), Cesamet®(Nabilone), Sativex® (Nabiximols)
Psychiatric disorders: Post-traumatic stress disorder (PTSD)
Addiction: achieving abstinence from cannabis dependence
Marinol®(Dronabinol), Sativex® (Nabiximols), CBD
Psychiatric disorders: Alcohol and opioid withdrawal symptoms
Psychiatric disorders: Schizophrenia and psychosis
Alzheimer‘s disease and dementia
Inflammation: Inflammatory skin diseases (dermatitis, psoriasis, pruritus)
Gastrointestinal system disorders: Irritable bowel syndrome
Gastrointestinal system disorders: Inflammatory bowel diseases (Crohn’s disease, ulcerative colitis)
THC, CBD, cannabis, CBG
Gastrointestinal system disorders: Diseases of the liver (hepatitis, fibrosis, steatosis, ischemia-reperfusion injury, hepatic encephalopathy)
Gastrointestinal system disorders: Metabolic syndrome, obesity, diabetes
THCV, THC, CBD, CBN
Anti-neoplastic properties (Cancer)
THC, CBD, CBG
[41, 142, 143]
The Benefits of Cannabis:
There is conclusive or substantial evidence that cannabis or cannabinoids are effective:
- For the treatment of chronic pain in adults (cannabis)
- As antiemetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids)
- For improving patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids)
- Increasing appetite and decreasing weight loss associated with HIV/AIDS (cannabis and oral cannabinoids)
There is moderate evidence that cannabis or cannabinoids are effective for:
- Improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis (cannabinoids, primarily nabiximols)
There is limited evidence that cannabis or cannabinoids are effective for：
- Improving clinician-measured multiple sclerosis spasticity symptoms (oral cannabinoids)
Improving symptoms of Tourette syndrome (THC capsules)
- Improving anxiety symptoms, as assessed by a public speaking test, in individuals with social anxiety disorders (CBD)
- Improving symptoms of posttraumatic stress disorder (nabilone; a single, small fair-quality trial)
(Cited and modified from [41, 42])
Therapeutic effects of THC
Therapeutic effects of CBD
Is cannabis a leading cause of death?
To put things into perspective, here are the leading causes for deaths from drugs in the United States:
- Tobacco…around 480,000 per year in the United States, and more than 7 million per year worldwide .
- Alcohol… around 95,000 per year in the United States .
- Prescription opioid analgesics …15,000 in 2018 in the United States .
- Non-steroidal anti-inflammatory drugs (NSAID)…3,200 per year in the 1990s .
- Cannabis (Marihuana)… nearly none reported as direct cause of death [177–179]
LD50 or Lethal Dose of Toxicity
Median lethal dose (LD50) is a standard measurement of acute toxicity in milligrams (mg) per kilogram (kg) of body weight . LD50 of a substance represents the individual dose that is required to kill 50 percent of a population when taken at once. Every chemical has an LD50 – for instance, the LD50 of caffeine is 150 to 200 milligrams per kilogram of body mass, or equivalent to 118 cups of coffee, and the LD50 of water is 90000 mg/kg of body mass, or around 6 litres. The lower the LD50 dose, the more toxic the substance.
If we were to examine THC, which is considered to be the compound with the highest toxicity in cannabis , the LD50 of oral THC in rats was 800-1910 mg/kg . There are no death records due to THC toxicity in dogs or monkeys . The LD50 for human remains unknown because there have been only several recorded deaths attributed to cannabis overdose consumption [177–179]. An estimate of the LD50 for THC in humans is equivalent to consuming about 1,500 pounds (680kg) of cannabis herb within 15 minutes , and an estimated intravenous lethal dose in humas is around 30mg/kg . Because the insolubility of cannabinoids in water, cannabis is usually smoked and orally administrated instead of injected intravenously .
Another study assessed the harm of drugs of potential misuse of 20 drugs and substances in terms of physical harm, dependence, and social harms . Cannabis was ranked 11th in dependence, 17th in physical harm, and 10th in social harm, ranking behind heroin, cocaine, alcohol, and tobacco.
There are experimental approaches suggest that opioids, NSAIDs and cannabinoids should be used in conjunction with one another to achieve improved pain relief with reduced dependency and side effects .
Overall, the toxicity of cannabis and cannabinoids is considered to be low, especially when compared to other abusive substances, even prescription drugs .
Adverse effects of cannabis
- Heavy marijuana use (daily or near-daily) can damage memory, learning, and attention, which can last a week or more after the last time someone used.
- Using marijuana during pregnancy or while breastfeeding may harm the baby, just like alcohol or tobacco.
- Marijuana use has been linked to anxiety, depression, and schizophrenia, but scientists don’t yet know whether it directly causes these diseases.
- Smoking any product, including marijuana, can damage your lungs and cardiovascular system.
Our scientists have been actively conducting research in searching for genetic markers, chemotype markers, and phenotypic markers that can be leveraged to select and distinguish cannabis strains to ensure identity, consistency, and traceability in manufacturing cannabis-based Natural Health Products and medicines. These fingerprint markers can facilitate the proprietary technology platform, GenBioChem® Triple Fingerprinting Technology™, which ensures quality, authenticity and purity throughout our entire production cycle from lab to shelf. We have also established and standardized the testing protocols for a full spectrum of secondary metabolites, including 14 cannabinoids, 45 terpenoids, 7 flavonoids, 3 sterols, and 3 triterpenoids, to innovatively develop cannabis-based natural health products and medications utilizing each part of cannabis plants. Several cutting-edge genetical and analytical technologies are involved in this technology platform and the related work has been published on peer-reviewed journals.
List of publications
- Jin, D., Jin, S., Yu, Y., Lee, C. & Chen, J. Classification of Cannabis Cultivars Marketed in Canada for Medical Purposes by Quantification of Cannabinoids and Terpenes Using HPLC-DAD and GC-MS. J Anal Bioanal Tech 8, 2 (2017).
- Jin, D., Jin, S. & Chen, J. Cannabis Indoor Growing Conditions, Management Practices, and Post-Harvest Treatment: A Review. American Journal of Plant Sciences 10, 925–946 (2019).
- Jin, D., Dai, K., Xie, Z. & Chen, J. Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes. Scientific Reports 10, 3309 (2020).
- Henry, P. et al. A single nucleotide polymorphism assay sheds light on the extent and distribution of genetic diversity, population structure and functional basis of key traits in cultivated north American cannabis. Journal of Cannabis Research 2, 26 (2020).
Jin, D., Henry, P., Shan, J. & Chen, J. Identification of Phenotypic Characteristics in Three Chemotype Categories in the Genus Cannabis. HortScience 1, 1–10 (2021).
- (Presenter) “Cannabis, the Herbal Medicine”, NHPRS (Natural Health Product Research Society of Canada) Annual Conference, London, Ontario, Aug. 14-17, 2015
- (Presenter) “Cannabis Classification Systems and Growth Trends of the North American Medical Cannabis Industry”, Second Annual Conference of TCM Pharmacognosy of WFCMS (World Federation of Chinese Medicine Societies), Wuhan, China, Oct. 24-26, 2015
- (Presenter) “A Chemotaxonomic Study of Medicinal Cannabis Marketed in Canada”, The International Conference on Analytical & Bio analytical Techniques conference, Orlando, USA, Sep. 29, 2016
- (Presenter) “Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stalk, and Roots for Medicinal Purposes”, Vitafoods Europe Summit, Geneva, Switzerland, May 8, 2019
- Mikuriya TH (1969) Marijuana in medicine: past, present and future. Calif Med 110:34–40
- Zuardi AW (2006) History of cannabis as a medicine: a review. Rev Bras Psiquiatr 28:153–157
- Brand EJ, Zhao Z (2017) Cannabis in Chinese Medicine: Are Some Traditional Indications Referenced in Ancient Literature Related to Cannabinoids? Front Pharmacol. https://doi.org/10.3389/fphar.2017.00108
- Ryz NR, Remillard DJ, Russo EB (2017) Cannabis Roots: A Traditional Therapy with Future Potential for Treating Inflammation and Pain. Cannabis Cannabinoid Res 2:210–216
- Brand E, Wiseman N (2008) Concise Chinese materia medica. Paradigm Publications, Taos, N.M.
- Smith FP, Stuart GA (1911) Chinese materia medica: vegetable kingdom. American Presbyterian Mission Press, Shanghai
- Fankhauser M (2002) History of cannabis in Western Medicine. In: Cannabis Cannabinoids. The Haworth Integrative Healing Press, New York, p Chapter 4. p. 37-51.
- Bache GBW a. F (1851) The Pharmacopoeia of the United States of America. Mack Print.
- Gaoni Y, Mechoulam R (1964) Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish. J Am Chem Soc 86:1646–1647
- Mechoulam R, Shvo Y (1963) Hashish—I: The structure of Cannabidiol. Tetrahedron 19:2073–2078
- ElSohly MA, Gul W (2014) Constituents of Cannabis Sativa. In: Handb. Cannabis. Oxford University Press, pp 3–22
- ElSohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 78:539–548
- Jin D, Dai K, Xie Z, Chen J (2020) Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes. Sci Rep 10:3309
- Pollastro F, Minassi A, Fresu LG (2018) Cannabis Phenolics and their Bioactivities. Curr Med Chem 25:1160–1185
- Ross SA, ElSohly MA, Sultana GN, Mehmedic Z, Hossain CF, Chandra S (2005) Flavonoid glycosides and cannabinoids from the pollen of Cannabis sativa L. Phytochem Anal Int J Plant Chem Biochem Tech 16:45–48
- Russo EB, Marcu J (2017) Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. In: Cannabinoid Pharmacol. Elsevier, pp 67–134
- Turner CE, Elsohly MA, Boeren EG (1980) Constituents of Cannabis sativa L. XVII. A review of the natural constituents. J Nat Prod 43:169–234
- Hampson AJ, Grimaldi M, Axelrod J, Wink D (1998) Cannabidiol and (-) Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci 95:8268–8273
- Eubanks LM, Rogers CJ, Beuscher IV AE, Koob GF, Olson AJ, Dickerson TJ, Janda KD (2006) A molecular link between the active component of marijuana and Alzheimer’s disease pathology. Mol Pharm 3:773–777
- Volicer L, Stelly M, Morris J, McLAUGHLIN J, Volicer BJ (1997) Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 12:913–919
- Xiao R-Y, Wu L-J, Hong X-X, Tao L, Luo P, Shen X-C (2018) Screening of analgesic and anti-inflammatory active component in Fructus Alpiniae zerumbet based on spectrum–effect relationship and GC–MS. Biomed Chromatogr 32:e4112
- Rufino AT, Ribeiro M, Judas F, Salgueiro L, Lopes MC, Cavaleiro C, Mendes AF (2014) Anti-inflammatory and chondroprotective activity of (+)-α-pinene: structural and enantiomeric selectivity. J Nat Prod 77:264–269
- Kim D-S, Lee H-J, Jeon Y-D, Han Y-H, Kee J-Y, Kim H-J, Shin H-J, Kang J, Lee BS, Kim S-H (2015) Alpha-pinene exhibits anti-inflammatory activity through the suppression of MAPKs and the NF-κB pathway in mouse peritoneal macrophages. Am J Chin Med 43:731–742
- Andre CM, Evers YL and D (2010) Dietary Antioxidants and Oxidative Stress from a Human and Plant Perspective: A Review. In: Curr. Nutr. Food Sci. Accessed 13 Dec 2019
- Russo EB (2011) Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 163:1344–1364
- Blasco-Benito S, Seijo-Vila M, Caro-Villalobos M, et al (2018) Appraising the “entourage effect”: Antitumor action of a pure cannabinoid versus a botanical drug preparation in preclinical models of breast cancer. Biochem Pharmacol 157:285–293
- McPartland JM, Russo EB (2001) Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts? J Cannabis Ther 1:103–132
- Baram L, Peled E, Berman P, Yellin B, Besser E, Benami M, Louria-Hayon I, Lewitus GM, Meiri D (2019) The heterogeneity and complexity of Cannabis extracts as antitumor agents. Oncotarget 10:4091–4106
- United Nations Office on Drugs, Crime (2009) Recommended Methods for the Identification and Analysis of Cannabis and Cannabis Products. UN
- Hillig KW (2005) A systematic investigation of Cannabis, PhD thesis, Indiana University. PhD Thesis
- Linnaeus C (1753) Species Plantarum 2: 1057. Laurentii Salvii, Stockholm
- McPartland JM (2017) Cannabis sativa and Cannabis indica versus “Sativa” and “Indica.” In: Cannabis Sativa -Bot. Biotechnol. Springer, pp 101–121
- de Lamarck JB (1785) Encyclopédie Méthodique de Botanique, vol. 1, pt. 2. Paris, France, pp. 694–695.
- Clarke RC, Merlin MD (2013) Cannabis: Evolution and Ethnobotany, 1st ed. University of California Press
- Anderson LC (1980) Leaf variation among cannabis species from a controlled garden. Bot Mus Leafl Harv Univ 28:61–69
- Small E, Beckstead HD (1973) Letter: Cannabinoid phenotypes in Cannabis sativa. Nature 245:147–148
- Small E, Beckstead HD (1973) Common cannabinoid phenotypes in 350 stocks of Cannabis. Lloydia 36:144–165
- Fournier G, Richez-Dumanois C, Duvezin J, Mathieu JP, Paris M (1987) Identification of a new chemotype in Cannabis sativa: cannabigerol-dominant plants, biogenetic and agronomic prospects. Planta Med 53:277–280
- Mandolino G, Carboni A (2004) Potential of marker-assisted selection in hemp genetic improvement. Euphytica 140:107–120
- Canada H (2018) Licensed cultivators, processors and sellers of cannabis under the Cannabis Act. In: aem. https://www.canada.ca/en/health-canada/services/drugs-medication/cannabis/industry-licensees-applicants/licensed-cultivators-processors-sellers.html. Accessed 2 Dec 2020
- National Academies of Sciences E (2017) The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. https://doi.org/10.17226/24625
- Health Canada (2013) Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids [Health Canada, 2013]. In: aem. Accessed 30 Sep 2018
- Martin R. Tramèr, Dawn Carroll, Fiona A. Campbell, D. John M. Reynolds, R. Andrew Moore, Henry J. McQuay (2001) Cannabinoids For Control Of Chemotherapy Induced Nausea And Vomiting: Quantitative Systematic Review. BMJ 323:16
- Machado Rocha FC, Stefano SC, De Cassia Haiek R, Rosa Oliveira LMQ, Da Silveira DX (2008) Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care (Engl) 17:431–443
- Phillips RS, Friend AJ, Gibson F, Houghton E, Gopaul S, Craig JV, Pizer B (2016) Antiemetic medication for prevention and treatment of chemotherapy-induced nausea and vomiting in childhood. Cochrane Database Syst Rev 2:CD007786
- Whiting PF, Wolff RF, Deshpande S, et al (2015) Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA 313:2456–2473
- Smith LA, Azariah F, Lavender VTC, Stoner NS, Bettiol S (2015) Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database Syst Rev CD009464
- Beal JE, Olson R, Laubenstein L, Morales JO, Bellman P, Yangco B, Lefkowitz L, Plasse TF, Shepard KV (1995) Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 10:89–97
- Beal JE, Olson R, Lefkowitz L, et al (1997) Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage 14:7–14
- Haney M, Gunderson EW, Rabkin J, Hart CL, Vosburg SK, Comer SD, Foltin RW (2007) Dronabinol and marijuana in HIV-positive marijuana smokers: caloric intake, mood, and sleep. JAIDS J Acquir Immune Defic Syndr 45:545–554
- Lutge EE, Gray A, Siegfried N (2013) The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database Syst Rev CD005175
- Wade DT, Makela PM, House H, Bateman C, Robson P (2006) Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler J 12:639–645
- C. C, P. D, I. K. M, S. R (2007) Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 14:290–296
- Bloomfield EL (2009) Tetrahydrocannabinol (Delta 9-THC) Treatment in Chronic Central Neuropathic Pain and Fibromyalgia Patients: Results of a Multicenter Survey. Anesthesiol Res Pract 1–9
- Koppel BS, Brust JCM, Fife T, Bronstein J, Youssof S, Gronseth G, Gloss D (2014) Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 82:1556–1563
- Gordon E, Devinsky O (2001) Alcohol and Marijuana: Effects on Epilepsy and Use by Patients with Epilepsy. Epilepsia 42:1266–1272
- Gloss D, Vickrey B (2012) Cannabinoids for epilepsy. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD009270.pub2
- Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG (2014) Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55:791–802
- Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F (2016) Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 15:270–278
- Whalley B, Stephens G, Williams C, Guy G, Wright S, Kikuchi T (2015) Use of one or a combination of phyto-cannabinoids in the treatment of epilepsy. US Patent US9066920B2.
- M. Kalkach-Aparicio, M. Cuéllar-Herrera, E.L. Flores-Ramírez, P. Ruíz-Gadea, L. Medina-Osti, D. Trejo-Martínez, F. Velasco, G. Aguado, A.L. Velasco, G. Gorian-Montealegre (2016) The use of cannabis as an antiepileptic treatment in Mexico: A review, bioethical analysis, discussion and position of the Hospital General de México Epilepsy Clinic. Rev Médica Hosp Gen México 79:68–78
- Rosenberg EC, Louik J, Conway E, Devinsky O, Friedman D (2017) Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol. Epilepsia 58:e96–e100
- Billakota S, Devinsky O, Marsh E (2019) Cannabinoid therapy in epilepsy. Curr Opin Neurol 32:220–226
- Ferreiros A, Beltrán-Carrascal E, Restrepo P, Pantoja C, Castañeda-Cardona C, Lasalvia P, Van der Werf L, Nariño D, Rosselli D (2020) Efficacy of cannabinoids in pharmacoresistant epilepsy: A narrative review of the literature. Iatreia 33:167–176
- Nabbout R, Thiele EA (2020) The role of cannabinoids in epilepsy treatment: a critical review of efficacy results from clinical trials. Epileptic Disord Int Epilepsy J Videotape 22:23–28
- Redmond WJ, Goffaux P, Potvin S, Marchand S, Redmond WJ, Goffaux P, Potvin S, Marchand S (2008) Analgesic and antihyperalgesic effects of nabilone on experimental heat pain. Curr Med Res Opin 24:1017–1024
- Niesink RJM, van Laar MW (2013) Does Cannabidiol Protect Against Adverse Psychological Effects of THC? Front Psychiatry. https://doi.org/10.3389/fpsyt.2013.00130
- Jain AK, Ryan JR, McMahon FG, Smith G (1981) Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol 21:320S-326S
- Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ (2003) Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain 106:169–172
- Beaulieu P (2006) Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth 53:769–775
- Holdcroft A, Maze M, Doré C, Tebbs S, Thompson S (2006) A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology 104:1040–1046
- Comelli F, Giagnoni G, Bettoni I, Colleoni M, Costa B (2008) Antihyperalgesic Effect of a Cannabis sativa Extract in a Rat Model of Neuropathic Pain : Mechanisms Involved. PTR Phytother Res 22:1017–1024
- Lynch ME, Campbell F (2011) Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol 72:735–744
- Johal H, Devji T, Chang Y, Simone J, Vannabouathong C, Bhandari M (2020) Cannabinoids in Chronic Non-Cancer Pain: A Systematic Review and Meta-Analysis. Clin Med Insights Arthritis Musculoskelet Disord 13:1–13
- Stockings E, Campbell G, Hall WD, Nielsen S, Zagic D, Rahman R, Murnion B, Farrell M, Weier M, Degenhardt L (2018) Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. Pain 159:1932–1954
- Noyes R, Brunk SF, Baram DA, Canter A (1975) Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 15:139–143
- Noyes R, Brunk SF, Avery DA, Canter AC (1975) The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 18:84–89
- Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT (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
- Guindon J, Lai Y, Takacs SM, Bradshaw HB, Hohmann AG (2013) Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment. Pharmacol Res 67:94–109
- Esin E, Yalcin S (2014) Neuropathic cancer pain: What we are dealing with? How to manage it? OncoTargets Ther 7:599–618
- Lynch ME, Cesar-Rittenberg P, Hohmann AG (2014) A Double-Blind, Placebo-Controlled, Crossover Pilot Trial With Extension Using an Oral Mucosal Cannabinoid Extract for Treatment of Chemotherapy-Induced Neuropathic Pain. J Pain Symptom Manage 47:166–173
- Blanton HL, Brelsfoard J, DeTurk N, Pruitt K, Narasimhan M, Morgan DJ, Guindon J (2019) Cannabinoids: Current and Future Options to Treat Chronic and Chemotherapy-Induced Neuropathic Pain. Drugs 79:969–995
- Johnson JR, Lossignol D, Burnell-Nugent M, Fallon MT (2013) An Open-Label Extension Study to Investigate the Long-Term Safety and Tolerability of THC/CBD Oromucosal Spray and Oromucosal THC Spray in Patients With Terminal Cancer-Related Pain Refractory to Strong Opioid Analgesics. J Pain Symptom Manage 46:207–218
- King KM, Myers AM, Soroka-Monzo AJ, Tuma RF, Tallarida RJ, Walker EA, Ward SJ (2017) Single and combined effects of Δ9 -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain. Br J Pharmacol 174:2832–2841
- Napchan U, Buse DC, Loder EW (2011) The Use of Marijuana or Synthetic Cannabinoids for the Treatment of Headache. Headache 51:502–505
- Rani Sagar D, Staniaszek LE, Kendall DA, et al (2010) Tonic Modulation of Spinal Hyperexcitability by the Endocannabinoid Receptor System in a Rat Model of Osteoarthritis Pain. Arthritis Rheum 62:3666–3676
- Schuelert N, Mcdougall JJ (2008) Cannabinoid-Mediated Antinociception Is Enhanced in Rat Osteoarthritic Knees. Arthritis Rheum 58:145–153
- Schuelert N, Johnson MP, Oskins JL, Jassal K, Chambers MG, McDougall JJ (2011) Local application of the endocannabinoid hydrolysis inhibitor URB597 reduces nociception in spontaneous and chemically induced models of osteoarthritis. Pain 152:975–981
- Richards BL, Whittle SL, Buchbinder R (2012) Neuromodulators for pain management in rheumatoid arthritis. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD008921.pub2
- Blake DR, Robson P, Ho M, Jubb RW, Mccabe CS (2006) Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatol Oxf Print 45:50–52
- Fiz J, Durán M, Capellà D, Carbonell J, Farré M (2011) Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life. PloS One 6:e18440
- Schley M, Legler A, Skopp G, et al (2006) Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief. Curr Med Res Opin 22:1269–1276
- Skrabek RQ, Galimova L, Ethans K, Perry D (2008) Nabilone for the Treatment of Pain in Fibromyalgia. J Pain 9:164–173
- Ware MA, Fitzcharles M-A, Joseph L, Shir Y (2010) The Effects of Nabilone on Sleep in Fibromyalgia: Results of a Randomized Controlled Trial. Anesth Analg 110:604–610
- Weber M, Goldman B, Truniger S (2010) Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: a randomised, double-blind crossover trial. J Neurol Neurosurg Psychiatry 81:1135–1140
- Colasanti BK (1990) A comparison of the ocular and central effects of delta 9-tetrahydrocannabinol and cannabigerol. J Ocul Pharmacol 6:259–269
- Nguyen BM, Kim D, Bricker S, Bongard F, Neville A, Putnam B, Smith J, Plurad D (2014) Effect of marijuana use on outcomes in traumatic brain injury. Am Surg 80:979–983
- Mario DN, Alicia M. Z, Daniel A. G, Luca M, Floris H.B.M. S, Aurel P-W, Réza B (2016) Prior Cannabis Use Is Associated with Outcome after Intracerebral Hemorrhage. Cerebrovasc Dis 41:248–255
- Williams SJ, Hartley JP, Graham JD (1976) Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients. Thorax 31:720–723
- Hartley JP, Nogrady SG, Seaton A (1978) Bronchodilator effect of delta1-tetrahydrocannabinol. Br J Clin Pharmacol 5:523–525
- Tashkin DP, Shapiro BJ, Lee YE, Harper CE (1976) Subacute Effects of Heavy Marihuana Smoking on Pulmonary Function in Healthy Men. N Engl J Med 294:125–129
- Davies BH, Radcliffe S, Seaton A, Graham JD (1975) A trial of oral delta-1-(trans)-tetrahydrocannabinol in reversible airways obstruction. Thorax 30:80–85
- Gong H, Tashkin DP, Calvarese B (1983) Comparison of bronchial effects of nabilone and terbutaline in healthy and asthmatic subjects. J Clin Pharmacol 23:127–133
- Pacher P, Batkai S, Kunos G (2005) Cardiovascular pharmacology of cannabinoids. Cannabinoids 168:599–625
- Crawford WJ, Merritt JC (1979) Effects of tetrahydrocannabinol on arterial and intraocular hypertension. Int J Clin Pharmacol Biopharm 17:191–196
- Jetly R, Heber A, Fraser G, Boisvert D (2015) The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: A preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology 51:585–588
- Hindocha C, Cousijn J, Rall M, Bloomfield M a. P (2020) The Effectiveness of Cannabinoids in the Treatment of Posttraumatic Stress Disorder (PTSD): A Systematic Review. J Dual Diagn 16:120
- Morgan CJA, Das RK, Joye A, Curran HV, Kamboj SK (2013) Cannabidiol reduces cigarette consumption in tobacco smokers: Preliminary findings. Addict Behav 38:2433–2436
- Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV (2011) Dronabinol for the treatment of cannabis dependence: A randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend 116:142–150
- David J. A, Jan C, Nicholas L, et al (2014) Nabiximols as an Agonist Replacement Therapy During Cannabis Withdrawal: A Randomized Clinical Trial. JAMA Psychiatry 71:281–291
- Pava MJ, Woodward JJ (2012) A review of the interactions between alcohol and the endocannabinoid system: Implications for alcohol dependence and future directions for research. Alcohol 46:185–204
- Deikel SM, Carder B (1976) Attentuation of precipitated abstinence in methadone-dependent rats by delta9-THC. Psychopharmacol Commun 2:61–65
- Vela G, Fuentes JA, Bonnin A, Fernández-Ruiz J, Ruiz-Gayo M (1995) Perinatal exposure to delta 9-tetrahydrocannabinol (delta 9-THC) leads to changes in opioid-related behavioral patterns in rats. Brain Res 680:142–147
- Yamaguchi T, Hagiwara Y, Tanaka H, Sugiura T, Waku K, Shoyama Y, Watanabe S, Yamamoto T (2001) Endogenous cannabinoid, 2-arachidonoylglycerol, attenuates naloxone-precipitated withdrawal signs in morphine-dependent mice. Brain Res 909:121–126
- Reiman Amanda (2009) Cannabis as a substitute for alcohol and other drugs. Harm Reduct J 6:35–35
- McLoughlin BC, Pushpa‐Rajah JA, Gillies D, Rathbone J, Variend H, Kalakouti E, Kyprianou K (2014) Cannabis and schizophrenia. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD004837.pub3
- Krishnan S, Cairns R, Howard R (2009) Cannabinoids for the treatment of dementia. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD007204.pub2
- van den Elsen GAH, Ahmed AIA, Lammers M, Kramers C, Verkes RJ, van der Marck MA, Rikkert MGMO (2014) Efficacy and safety of medical cannabinoids in older subjects: A systematic review. Ageing Res Rev 14:56–64
- Charernboon T, Lerthattasilp T, Supasitthumrong T (2020) Effectiveness of Cannabinoids for Treatment of Dementia: A Systematic Review of Randomized Controlled Trials. Clin Gerontol 0:1–9
- Paunescu H, Dima L, Ghita I, Coman L, Ifteni PI, Fulga I, Coman OA (2020) A Systematic Review of Clinical Studies on the Effect of Psychoactive Cannabinoids in Psychiatric Conditions in Alzheimer Dementia. Am J Ther 27:e249–e269
- Bloomfield MAP, Green SF, Hindocha C, et al (2020) The effects of acute cannabidiol on cerebral blood flow and its relationship to memory: An arterial spin labelling magnetic resonance imaging study. J Psychopharmacol Oxf Engl 269881120936419
- Dvorak M, Watkinson A, McGlone F, Rukwied R (2003) Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin. Inflamm Res Off J Eur Histamine Res Soc Al 52:238–245
- Rukwied R, Watkinson A, Mcglone F, Dvorak M (2003) Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain Amst 102:283–288
- Watson ES, Murphy JC, Turner CE (1983) Allergenic properties of naturally occurring cannabinoids. J Pharm Sci 72:954–955
- Williams C, Thompstone J, Wilkinson M (2008) Work-related contact urticaria to Cannabis sativa. Contact Dermatitis 58:62–63
- Esfandyari T, Camilleri M, Ferber I, Burton D, Baxter K, Zinsmeister AR (2006) Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: a randomized, placebo-controlled study. Neurogastroenterol Motil 18:831–838
- Esfandyari T, Camilleri M, Busciglio I, Burton D, Baxter K, Zinsmeister AR (2007) Effects of a cannabinoid receptor agonist on colonic motor and sensory functions in humans : a randomized, placebo-controlled study. Am. J. Physiol. Gastrointest. Liver Physiol. 56:
- Wong BS, Camilleri M, Busciglio I, Carlson P, Szarka LA, Burton D, Zinsmeister AR (2011) Pharmacogenetic Trial of a Cannabinoid Agonist Shows Reduced Fasting Colonic Motility in Patients With Nonconstipated Irritable Bowel Syndrome. Gastroenterology 141:1638–1647
- Wong BS, Camilleri M, Eckert D, Carlson P, Ryks M, Burton D, Zinsmeister AR (2012) Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea. Neurogastroenterol Motil 24:358-e169
- Naftali T, Lev LB, Yablecovitch D, Half E, Konikoff FM (2011) Treatment of Crohn’s disease with cannabis: an observational study. Isr Med Assoc J IMAJ 13:455–458
- Lahat A, Lang A, Ben-Horin S (2012) Impact of cannabis treatment on the quality of life, weight and clinical disease activity in inflammatory bowel disease patients: a pilot prospective study. Digestion 85:1–8
- Engel MA, Kellermann CA, Burnat G, Hahn EG, Rau T, Konturek PC (2010) Mice lacking cannabinoid CB1-, CB2-receptors or both receptors show increased susceptibility to trinitrobenzene sulfonic acid (TNBS)-induced colitis. J Physiol Pharmacol Off J Pol Physiol Soc 61:89–97
- Jamontt JM, Molleman A, Pertwee RG, Parsons ME (2010) The effects of Delta-tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis. Br J Pharmacol 160:712–723
- Lal S, Prasad N, Ryan M, Tangri S, Silverberg MS, Gordon A, Steinhart H (2011) Cannabis use amongst patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 23:891–896
- Lim MP, Devi LA, Rozenfeld R (2011) Cannabidiol causes activated hepatic stellate cell death through a mechanism of endoplasmic reticulum stress-induced apoptosis. Cell Death Dis 2:e170–e170
- Mukhopadhyay P, Rajesh M, Horváth B, et al (2011) Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic Biol Med 50:1368–1381
- Avraham Y, Grigoriadis NC, Poutahidis T, Vorobiev’ L, Magen I, Ilan Y, Mechoulam R, Berry EM (2011) Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice. Br J Pharmacol 162:1650–1658
- Fouad AA, Jresat I (2011) Therapeutic potential of cannabidiol against ischemia/reperfusion liver injury in rats. Eur J Pharmacol 670:216–223
- Bátkai S, Mukhopadhyay P, Horváth B, et al (2012) Δ8-Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through cannabinoid CB2 receptors. Br J Pharmacol 165:2450–2461
- Riedel G, Fadda P, McKillop-Smith S, Pertwee RG, Platt B, Robinson L (2009) Synthetic and plant-derived cannabinoid receptor antagonists show hypophagic properties in fasted and non-fasted mice. Br J Pharmacol 156:1154–1166
- Levendal R-A, Schumann D, Donath M, Frost CL (2012) Cannabis exposure associated with weight reduction and β-cell protection in an obese rat model. Phytomedicine Int J Phytother Phytopharm 19:575–582
- Rocha FCM, dos Santos Júnior JG, Stefano SC, da Silveira DX (2014) Systematic review of the literature on clinical and experimental trials on the antitumor effects of cannabinoids in gliomas. J Neurooncol 116:11–24
- Borrelli F, Pagano E, Romano B, Panzera S, Maiello F, Coppola D, De Petrocellis L, Buono L, Orlando P, Izzo AA (2014) Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a Cannabis-derived non-psychotropic cannabinoid. Carcinogenesis 35:2787–2797
- Martin BR, Mechoulam R, Razdan RK (1999) Discovery and characterization of endogenous cannabinoids. Life Sci 65:573–595
- Rahn EJ, Hohmann AG (2009) Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics 6:713–737
- Leo E. Hollister (1971) Marihuana in Man: Three Years Later. Science 172:21
- Neff GW, O’Brien CB, Reddy KR, et al (2002) Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease. Am J Gastroenterol 97:2117–2119
- Kavia RBC, De Ridder D, Constantinescu CS, Stott CG, Fowler CJ (2010) Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler Houndmills Basingstoke Engl 16:1349–1359
- Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM (2015) Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 172:4790–4805
- Booz GW (2011) Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic Biol Med 51:1054–1061
- Mallada Frechín J (2018) Effect of tetrahydrocannabinol: cannabidiol oromucosal spray on activities of daily living in multiple sclerosis patients with resistant spasticity: a retrospective, observational study. Neurodegener. Dis. Manag.
- Callejas GH, Figueira RL, Gonçalves FLL, Volpe FAP, Zuardi AW, Crippa JA, Hallak JE, Sbragia L (2018) Maternal administration of cannabidiol promotes an anti-inflammatory effect on the intestinal wall in a gastroschisis rat model. Braz. J. Med. Biol. Res. 51:
- Couch DG, Tasker C, Theophilidou E, Lund JN, O’Sullivan SE (2017) Cannabidiol and palmitoylethanolamide are anti-inflammatory in the acutely inflamed human colon. Clin Sci 131:2611–2626
- Vallée A, Lecarpentier Y, Guillevin R, Vallée J-N (2017) Effects of cannabidiol interactions with Wnt/β-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer’s disease. Acta Biochim Biophys Sin 49:853–866
- Davis WM, Hatoum NS (1983) Neurobehavioral actions of cannabichromene and interactions with delta 9-tetrahydrocannabinol. Gen Pharmacol 14:247–252
- Cuñetti L, Manzo L, Peyraube R, Arnaiz J, Curi L, Orihuela S (2018) Chronic pain treatment with cannabidiol in kidney transplant patients in Uruguay. In: Transplant. Proc. Elsevier, pp 461–464
- Jones NA, Hill AJ, Smith I, Bevan SA, Williams CM, Whalley BJ, Stephens GJ (2010) Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J Pharmacol Exp Ther 332:569–577
- Klein BD, Jacobson CA, Metcalf CS, Smith MD, Wilcox KS, Hampson AJ, Kehne JH (2017) Evaluation of cannabidiol in animal seizure models by the Epilepsy Therapy Screening Program (ETSP). Neurochem Res 42:1939–1948
- Kaplan EH, Offermann EA, Sievers JW, Comi AM (2017) Cannabidiol treatment for refractory seizures in Sturge-Weber syndrome. Pediatr Neurol 71:18–23
- Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K (2018) Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet 391:1085–1096
- Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S (2017) Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 376:2011–2020
- Vilela LR, Lima IV, Kunsch ÉB, Pinto HPP, de Miranda AS, Vieira ÉLM, de Oliveira ACP, Moraes MFD, Teixeira AL, Moreira FA (2017) Anticonvulsant effect of cannabidiol in the pentylenetetrazole model: Pharmacological mechanisms, electroencephalographic profile, and brain cytokine levels. Epilepsy Behav 75:29–35
- Kaplan JS, Stella N, Catterall WA, Westenbroek RE (2017) Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci 114:11229–11234
- Rodríguez-Muñoz M, Onetti Y, Cortés-Montero E, Garzón J, Sánchez-Blázquez P (2018) Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor. Mol Brain 11:51
- Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, VanLandingham KE (2018) Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut Syndrome. N Engl J Med 378:1888–1897
- Ostrovsky DA, Ehrlich A (2018) Addition of cannabidiol to current antiepileptic therapy reduces drop seizures in children and adults with treatment-resistant Lennox-Gastaut syndrome. Explore J. Sci. Heal.
- Varadkar S (2018) Cannabidiol for drop seizures in Lennox-Gastaut syndrome. The Lancet 391:1006–1007
- Mannucci C, Navarra M, Calapai F, Spagnolo EV, Busardò FP, Cas RD, Ippolito FM, Calapai G (2017) Neurological aspects of medical use of cannabidiol. CNS Neurol Disord-Drug Targets Former Curr Drug Targets-CNS Neurol Disord 16:541–553
- Campos AC, Guimarães FS (2008) Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl) 199:223
- Resstel LB, Tavares RF, Lisboa SF, Joca SR, Corrêa FM, Guimarães FS (2009) 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 156:181–188
- Russo EB, Burnett A, Hall B, Parker KK (2005) Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 30:1037–1043
- Ligresti A, Moriello AS, Starowicz K, Matias I, Pisanti S, De Petrocellis L, Laezza C, Portella G, Bifulco M, Di Marzo V (2006) Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318:1375–1387
- CDCTobaccoFree (2020) Fast Facts. In: Cent. Dis. Control Prev. https://www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts/index.htm. Accessed 3 Dec 2020
- CDC (2020) Alcohol-Related Deaths. In: Cent. Dis. Control Prev. https://www.cdc.gov/alcohol/features/excessive-alcohol-deaths.html. Accessed 3 Dec 2020
- (2020) Overdose Death Maps | Drug Overdose | CDC Injury Center. https://www.cdc.gov/drugoverdose/data/prescribing/overdose-death-maps.html. Accessed 3 Dec 2020
- Tarone RE, Blot WJ, McLaughlin JK (2004) Nonselective Nonaspirin Nonsteroidal Anti-Inflammatory Drugs and Gastrointestinal Bleeding: Relative and Absolute Risk Estimates From Recent Epidemiologic Studies. Am J Ther 11:17–25
- Department of Health | The health and psychological consequences of cannabis use - chapter 1. https://www1.health.gov.au/internet/main/publishing.nsf/Content/health-pubs-drug-cannab2-ch1.htm. Accessed 3 Dec 2020
- Hartung B, Kauferstein S, Ritz-Timme S, Daldrup T (2014) Sudden unexpected death under acute influence of cannabis. Forensic Sci Int 237:e11–e13
- UNODC - Bulletin on Narcotics - 1972 Issue 2 - 002. In: U. N. Off. Drugs Crime. //www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1972-01-01_2_page003.html. Accessed 3 Dec 2020
- EPA - Ag 101, Lethal Dosage (LD50) Values. https://p2infohouse.org/ref/02/01244/www.epa.gov/agriculture/ag101/pestlethal.html. Accessed 3 Dec 2020
- Thompson GR, Rosenkrantz H, Schaeppi UH, Braude MC (1973) Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys. Toxicol Appl Pharmacol 25:363–372
- Annas GJ (1997) Reefer Madness — The Federal Response to California’s Medical-Marijuana Law. N Engl J Med 337:435–439
- Nutt D, King LA, Saulsbury W, Blakemore C (2007) Development of a rational scale to assess the harm of drugs of potential misuse. The Lancet 369:1047–1053
- Vanegas H, Vazquez E, Tortorici V (2010) NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System. Pharmaceuticals 3:1335–1347
- (2018) It’s legal in many states, so doesn’t that mean marijuana is safe? | FAQs | Marijuana | CDC. https://www.cdc.gov/marijuana/faqs/is-marijuana-safe-because-its-legal.html. Accessed 3 Dec 2020
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