- Weight Goals with Sue Galluzo
- Eat to Beat Inflammation
- A Better Butter Chicken
- Begin Your Day with Energy
- Smart Starts for Back to School
- Tropical Twister
- Tropical Cobb Salad
- Tomato Salad
- Homemade Hibiscus Cold Brew Tea
- When Tears are Not Enough
- Fajita Steak Platter
- Walking on Sunshine
- Olive Oil & Omega-3s
- Chimichurri Potato Salad
- Granate Berry
Medical Cannabis and Naturopathy
Toronto’s Canadian College of Naturopathic Medicine weighs in on medical cannabis and the current medical research.
Please seek care from your naturopath or family doctor to identify any contraindications with current medications or immediate care needs before self-medicating.
The genus Cannabis, commonly known as marihuana or marijuana, refers to a flowering plant of which there are 3 main species, Cannabissativa, Cannabis indicaand Cannabis ruderalis. It has received a lot of public and media attention since the announcement of legalization for recreational use in Canada.
Medical cannabis refers to using cannabis or cannabinoids as a medical therapy to treat disease or alleviate symptoms. In addition to requiring prescription and oversight from a healthcare provider with knowledge, skills, scope and competency, this may also differ from recreational use due to differences in product quality and consistituents.
Despite the fact that the herb Cannabis has been used for more than 3,000 years for the treatment and management of pain, digestive issues and psychological disorders by various cultures, many healthcare providers are somewhat familiar or experience discomfort with appropriate medicinal usage. A recent survey (1) of Canadian physicians revealed that dosing and the need for safe, effective treatment monitoring places were at the forefront of educational needs. This may be in part due to stigma, as well as significant changes in the volume and quality of both evidence and high quality products as well as the regulatory and legal policies surrounding its use (2). Although the list of conditions for approved medical use has been growing, the research to support many of these treatments is limited. To help further understand this plant, a brief review of the available evidence on its pharmacology and medical uses, along with the safety issue from the perspective of naturopathic medicine, is provided to help address gaps in knowledge or understanding.
Hemp grows throughout temperate and tropical climates but originated from central Asia or in the foothills of the Himalayas (3). The leaves and flowering tops of cannabis plants contain at least 489 distinct compounds known as cannabinoids distributed among 18 different chemical classes, and harbor more than 70 different phytocannabinoids (4). Many of these compounds interact with our bodies via the endocannabinoid system (5), where their actions are mainly mediated by their interaction with two closely related receptors, CB1 and CB2, first chemically identified in the 1940s (6,7). Potential for these receptor-mediated interactions are high, particularly throughout the central nervous system (CNS), with CB1 receptor being expressed in neurons and CB2 receptors being localized primarily on cells of the immune system.
Δ9-THC is by far the best studied phytocannabinoid, and is responsible for the psychoactive effects of cannabis through its actions at the CB1 receptor (8). It is the major psychoactive constituent and also has the largest association with tolerance and withdrawal effects. THC is regularly used to measure the herb’s potency. Typical concentrations of THC are less than 0.5% for inactive hemp, 2% to 3% for marijuana leaf, and up to 4-8% for higher-grade seedless, or sinsemilla buds. Higher concentrations can be found in extracts, tonics, and hashish (concentrated cannabisresin). THC displays complex psychoactive effects, analgesic, cognitive, muscle relaxant, anti-inflammatory, appetite stimulant and antiemetic activity (9).
Cannabidiol (CBD) is the main non-psychoactive phytocannabinoid in the cannabis plant that has drawn more attention in recent years. It does not have the intoxicating effects of THC, and it does not develop tolerance and withdrawal effects (10). Despite its weak affinity for the CB1 and CB2 receptors, CBD seems to antagonize CB1/CB2 receptor agonists in CB1 and CB2 expressing cells and tissues (11). Animal studies have demonstrated it has neuroprotective (12,13), anti-inflammatory, antioxidant properties (14), anticonvulsant, analgesic, anti-anxiety, antiemetic, immune-modulating and anti-tumorigenic properties. Preliminary clinical trials suggest that high-dose oral CBD (150–600 mg/d) may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but it may also cause mental sedation (15).
There is considerable variation in the consistency of constituents amongst Cannabis plants and species. In general, cannabis products (recreational and medicinal) derived from Cannabis sativa exhibit a higher CBD/THC ratio than products derived from Cannabis indica. Administering different ratios of THC and CBD leads to diverse outcomes. Experimental studies indicate CBD attenuates effects of ∆9-THC requiring at least 8 : 1 (±11.1) ratio of CBD to THC; whereas CBD appears to potentiate some of the effects associated with THC when the CBD to THC ratio is around 2 : 1 (±1.4) (16).
Use of Medical Cannabis:
Nausea and vomiting associated with cancer chemotherapy is one of the most familiar and well-established uses of cannabis in modern medicine. Cannabis is a potent antiemetic with therapeutic potential in cancer care(17). A systematic review and meta analysis of medicinal cannabis (18) found all studies suggested a greater benefit of cannabinoids compared to both active comparators and placebo, however no single study reached statistical significance. It is also important to note that paradoxically at excessive doses, Cannabis can precipitate cannabis hyperemesis syndrome (CHS) (19). This is relatively infrequent, but significant adverse reaction is characterized by severe nausea and vomiting followed by a period of deep sleep. For patients undergoing chemotherapy and radiation, THC is known to increase appetite, and subsequently weight, as an additional benefit.
The systematic reviews on the efficacy and safety of cannabis-based medicine for chronic pain conditions have yielded diverse conclusions. A recent systematic review (20) supported the effectiveness of cannabis in treating chronic pain, primarily for neuropathic pain patients. However, Häuser W et al (21), didn’t come to a conclusion of the effectiveness of cannabis based on the quality of the clinical trial, most critical challenge being the small size and short term of research design. A 2014 statement issued by The Canadian Pain Society (22) recommended cannabis-based medicines as a potential third-line treatment for chronic neuropathic pain; while the Canadian Agency for Drugs and Technologies in Health (23) (2016) reviewed clinical safety and effectiveness of cannabinoid buccal spray for chronic non-cancer or neuropathic pain and suggested there was insufficient evidence to make well-founded conclusions about the clinical advantage and use of cannabis-based medicines for the management of cancer and non-cancer pain.
Ocular (as well as systemic) administration of cannabinoids typically lowers intraocular pressure (IOP) by up to 30% although the mechanism is not well elucidated (24). A small but well-controlled pilot study of 6 patients with ocular hypertension or early primary open-angle glaucoma reported that two hours after sublingual administration of a single 5 mg Δ9-THC reduced the IOP significantly and was well tolerated by most patients. Sublingual 20 mg of CBD did not reduce IOP, while 40 mg of CBD increased IOP at four hours after administration (25).
The various needs and symptom profiles of patients with multiple sclerosis (MS) present with make it difficult to assess the observed and potential effectiveness of cannabis. Pharmaceutical CBD have been investigated for its effectiveness and safety in treating MS. A recent systematic review (26)supports the clinical use of CBD for spasticity and pain in multiple sclerosis, while it is not inconclusive on use to treat other common symptoms like bladder control, ataxia and tremor. Adverse effects including dizziness, dry mouth, euphoria, diarrhea, and difficulty concentrating were most frequently described as “mild” to “moderate”. Some researchers argued that a risk/benefit decision may be needed in the management of CBD used by MS patients. According to another study (27), the benefitsof CBD were generally observed within the first 4 weeks; thus a trial of 4-6 weeks is recommended to determined whether patients will receive clinical benefit.
Compared with THC, that has been found to induce anxiety in healthy subjects (28), CBD has been drawing more attention in treating most of anxiety due to its anxiolytic property (29) without impairing cognitive performance (30). Increasing doses of CBD leads to a linear reduction in anxiety, compared with the biphasic anxiolytic/anxiogenic effect of THC use (31). A double-blind randomized design study (32) on 24 patients with generalized social anxiety disorder (SAD) demonstrated that 600mg orally pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, compared with the placebo group. A fMRI study on fifteen healthy men found that oral administration of 600mg CBD and 10mg D-9-THC presented opposite neurophysiological effects when performing different cognitive task; while the following behavioral experiment on six healthy volunteers, after pretreatments of 5mg CBD intravenously (IV) followed by 1.25 mg IV D-9-THC prevented the acute induction of psychotic symptoms, thus might lessen the anxiogenic effects of THC (33).
Cannabis preparations have reported to be beneficial in treatment of epilepsy and other seizure disorders, particularly drug refractory childhood epilepsies. Cannabis products with moderate to high THC content are generally unsuitable for this condition, considering the potential risk of seizure aggravation (34) and undesired side effects such as psychiatric disorders, addiction liability, cognitive and motor impairment in the childhood population. CBD, on the other hand, shows a promising anticonvulsant profile in the recent high quality RCT trials. The efficacy of CBD as add-on therapy for patients with Dravet syndrome (35) and drop seizure in patients with Lennox-Gastaut syndrome (36) were investigated. The results of these studies demonstrate that, at a dosage of 20 mg/kg/day, add-on CBD was efficacious in reducing the frequency of convulsive seizures. The CBD group was had higher adverse events such as diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting, but generally well tolerant. As seen in other disorders, this case illustrates that the risk: benefit profile of cannabinoids needs to be weighed and discussed with patients prior to initiating therapy. Current best practices do not suggest CBD as stand-alone monotherapy in seizure disorders.
According to the studies, different doses of THC yields mixed results. A low dose of THC (less than 5 mg) seems to increase the quality of sleep and reduce the frequency of nightmares (37) while administration of larger dose (15mg) decreased sleep latency on the following morning, and disturbed both mood and memory on the next day. Novel studies investigating cannabinoids and obstructive sleep apnea suggest that synthetic cannabinoids such as nabilone and dronabinol may have short-term benefit for sleep apnea due to their modulatory effects on serotonin-mediated apneas. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, while nabilone may reduce nightmares associated with Post-traumatic stress disorder (PTSD) and may improve sleep among patients with chronic pain.
Chronic cannabisuse is associated with negative subjective effects on sleep that are manifested most prominently during withdrawal. Symptoms reported include sleep difficulties such as strange dreams, insomnia, and poor sleep quality.
These results are consistent with one interpretation that cannabis is typically not beneficial to sleep except among medicinal cannabisusers who are identified by the presence of pre-existing sleep interrupting symptoms such as pain. As such, cannabis may be thought to improve sleep via the mediating improvement of these confounding symptoms.
Methods for using Cannabis:
Cannabis can typically be administered by inhalation, oral ingestion, and topical application. Each delivery method has its advantages and disadvantages. The effects of cannabis are felt fastest when it is inhaled (i.e. liquid aerosol, nebulized or ‘smoked’). Inhalation is the most common way with the advantages of quick action, ease of monitoring the amount ingested, convenience, and short-term duration of effect. Side effects often include increasing risk of bronchitis and potential link to cancers of the respiratory tract, particularly when smoked. Vaporizing (liquid aerosol) has been considered safer than smoking because there are less by products since a lower temperature is used in the vaporizer and is thus a healthy alternative to smoking, however these statements deserve further investigation and evaluation. Cannabis oils and tinctures are examples of concentrates of cannabis taken orally. Compared to smoking, oral administration results in slower onset of action, lower blood levels of cannabinoids, and a longer duration of pharmacodynamic effects (38), though there is some indication that different oral forms (sublingual, food-product, ‘extended-release’) will have differing pharmacokinetic profiles. Topicals are one of the lesser known forms of medicinal cannabison the market, but they have significant potential to benefit people with inflammation and pain. The low THC content make them particularly attractive to consider for cannabis-naïve or cannabis-hesitant users. The other topical application is suppositories which can sometimes have some psychoactive effect depending on the product constituents.
Prescribed cannabis or cannabidiol approved by Health Canada includes Nabilone (commercial name of Cesamet®) and Dronabinol (commercial name of Marinol®) which are the orally administered synthetic structural analogues of Δ9-THC. The latter was discontinued in the Canadian market in 2012. Cesamet® is sold as capsules (0.25, 0.5, 1 mg) and is indicated for the treatment of the nausea and vomiting associated with cancer chemotherapy (39). Nabiximols (commercial name of Sativex®) is from a whole-plant extract of two different, but standardized, strains of Cannabis sativa containing approximately equivalent amounts of Δ9-THC (27 mg/mL) and CBD (25 mg/mL), and other cannabinoids. It is marketed as an adjunctive treatment for the symptomatic relief of spasticity and neuropathic pain in adults with multiple sclerosis and as an adjunctive analgesic in adult patients with advanced cancer who experience moderate to severe pain (40).
To date there has been no documented fatal overdose from isolated Cannabis use. These statistics are impressive if compared with other commonly used recreational drugs. Globally, alcohol was linked to over 3 million deaths per year in 2012, and tobacco is reportedly linked to the deaths ofmore than 6 million people each year (41). Although several toxicology studies (42,43) with THC in animals suggested that THC was considered a safe drug both in acute and long-term exposure, toxicity of the commercial synthetic cannabinoids was found to be increased compared with Cannabis itself (44). The side effects typically include: dizziness/light-headedness, sedation, confusion, ataxia, a feeling of intoxication, euphoria (“high”), xerostomia, dysgeusia, and hunger (20).
Ina residential laboratory study (45,46) on twelve daily marijuana smokers, the development of tolerance was evaluated after four-day period administration in two different groups including the oral THC pills group and the smoked marijuana group. Each pills contained 30 mg of THC and smoked marijuana dose consisted of 3.1% THC, and they were administrated four times a day in each group. Both groups became tolerant to subjective effects of THC such as feeling “high” and “good drug effect” but not to its effects on food intake or social behavior. The tolerance was disappears rapidly following cessation of administration (47). In addition, the dynamics of tolerance vary with respect to the different constituents and effects (48). However, some long-term studies reported the absence of pharmacological tolerance (49, 50)– this suggests that dosing straetgies may help alleviate or prevent issues of tolerance.
There is evidence that cannabis dependence (physical and psychological) occurs especially with chronic, heavy use (51). However, Cannabis is considered to be also far less addictive than alcohol, nicotine, cocaine, opiates and other psychoactive drugs. In the 1970’s, recreational cannabis became known as “the gateway drug,” but facts do not support this statement. In fact, studies suggest medical cannabis is a safer alternative rather than prescriptions of some pharmaceuticals with well-known potential for addiction (52).
Cannabis does have the potential to exacerbate symptoms of underlying conditions, such as severe cardiopulmonary disease because of occasional hypotension, possible hypertension, syncope, or tachycardia (53); Studies showed that although Cannabis smokers have minimal changes in pulmonary function studies as compared to tobacco smokers, they may develop bullous disease and spontaneous pneumothorax. The relationship between Cannabis smoking and lung cancer remains unclear due to design limitations of the studies published so far. Therefore, Health Canada stated in 2013, “smoked Cannabis is not recommended in patients with respiratory insufficiency such as asthma or chronic obstructive pulmonary disease (COPD)” (54).
- Cognitive function:
Evidence has demonstrated that high THC/low CBD Cannabis (55) lead to greater cognitive impairments, in particular memory function, attention and emotional processing in individuals. On the other hand, research showed CBD seems to antagonize THC-induced impairments and improve cognition in multiple preclinical models of cognitive impairment, including models of neuropsychiatric (schizophrenia), neurodegenerative (Alzheimer’s disease), neuro-inflammatory (meningitis, sepsis and cerebral malaria) and neurological disorders (hepatic encephalopathy and brain ischemia) (56). However it is unclear whether at specific concentrations CBD might outweigh any harmful effects of THC on cognition.
- Brain development:
The regular (mis)use of cannabis during developing childhood and adolescence is of particular concern and the question of whether Cannabis is harmful remains the subject of heated debate. Although multiple studies have reported the adverse effects of Cannabis use on mental health are greater during development, particularly during adolescence, than in adulthood (57), others studies (58) have not made definite conclusions as to whether cannabis use alone has a negative impact on the human adolescent brain (59). Given the uncertainty of potentially risks, “Cannabis should not be used in any person under the age of 18, and physicians in Ontario “are not allowed to prescribe Cannabis to patients under the age of 25 unless all other conventional therapeutic options have been attempted and have failed to alleviate the patient’s symptoms” (60).
- Mental health:
Whether the use of Cannabis might precipitate mental illness in some patients is a long standing concern. Cannabis has been linked to episodes of acute psychosis (61) and can exacerbate the symptoms of existing psychotic illness like schizophrenia (62, 63). However, some studies report the opposite results—CBD seems to represent a mechanistically different and less side-effect prone antipsychotic compound for the treatment of schizophrenia, even though the underlying pharmacological mechanisms are still debated (64). Given the uncertainty of results, Health Canada suggests “medicinal cannabis should not be used in patients with a personal history of psychiatric disorders (especially schizophrenia), or a familial history of schizophrenia” (65). In other conditions like anxiety disorders, the anxiolytic effects of Cannabis in clinical populations are inconsistent (65).
Legal access to treatment:
In Canada as of early 2017, Cannabis was legal only for medicinal purposes and only under conditions outlined in the Access to Cannabis for Medical Purposes Regulations (ACMPR) issued by Health Canada. Under the ACMPR, patients must receive medical documentation from their medical doctor to be eligible for medical Cannabis use. From there, they can decide whether they will register with one of Canada’s licensed producers (66) or register with Health Canada to produce a limited amount on their own (67)or have a caregiver produce it for them. Patients who are eligible to use medical Cannabis are only allowed to have a 30-day supply/150 grams of dried Cannabis (or the equivalent if in another form) at a time. Currently, naturopathic doctors in Canada are not authorized to prescribe any derivative of Cannabis including THC and CBD, which are both classified as a schedule 2 drug. However, given their education and holistic approach, naturopathic doctors could play a critical role in patients’ care, including referring them to a physician or other care provider with scope, knowledge and skills to assist in securing a legal medical prescription for medical Cannabis. Future changes in regulatory scope and advanced training opportunities may facilitate opportunity for naturopathic doctors and other healthcare providers to provide safe and effective access to various medical Cannabis.
Propelled by the legalizing medicinal use of cannabis with a wide range of potential indications, cannabis-based medicines undoubtedly enrich the options for treatments of many conditions. Current research and the evidence base on cannabisis still in its infancy. The common drawbacks are small size sample, short term research duration and heterogeneity of the cannabis-based products. There is a huge demand for more rigorous clinical research to be done to further understand the effectiveness and safety in medicinal cannabis use. It remains the responsibility of the naturopathic medical community to not only be prepared and properly informed on the issues, but also to demand such change as soon as possible, for the sake of our patients.
I sincerely thank Dr. Paul Saunders, ND and Dr. Kieran Cooley, ND for their input on this manuscript.
- Ziemianski D, Capler R, Tekanoff R, Lacasse A, Luconi F, Ware MA. Cannabis in medicine: a national educational needs assessment among Canadian physicians.BMC Med Educ.2015 Mar 19;15:52.
- Isaac S, Saini B, Chaar BB. The Role of Medicinal Cannabis in Clinical Therapy: Pharmacists’ Perspectives.PLoS One.2016 May 12;11(5):e0155113.
- Elsohly M. Marijuana and the Cannabinoids. Totowa: Humana Press, 2007.
- Elsohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids.Life Sci.2005;78(5): 539-48.
- Lu HC, and Mackie K. An introduction to the endogenous cannabinoid system. Biol. Psychiatry.2016; 79(7): 516–25.
- Adams R. Marihuana: harvey lecture, February 19,1942. Bull N Acad Med. 1942;18 (11):705–30.
- Roger Adam and B.R.Baker. Structure of cannabidiol. VII. A method of synthesis of a tetrahydrocannabinol which possesses marihuana activity. J. Am. Chem. Soc. 1940;62(9): 2405–8.
- Hajos N, Ledent C, Freund TF. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience. 2001;106(1): 1-4.
- Benbadis SR, Sanchez-Ramos J, Bozorg A, et al. Medical marijuana inneurology. Expert Rev Neurother. 2014 ;14:1453-65.
- Bergamaschi MM, Queiroz HCR, Zuardi WA, Crippa AS: Safety and side effects of cannabidiol, a Cannabis sativa constituent. Curr Drug Saf 2011, 6:237-49.
- The diverse CB1 and CB2receptor pharmacology of three plantcannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.Br J Pharmacol. 2008 Jan;153(2):199-215.
- Esposito G, De FilippisD,Maiuri MC, De Stefano D, Carnuccio R, Iuvone T. 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. 2006; 399(1-2): 91–95.
- Hamelink C, Hampson A, Wink D. A, EidenLE, Eskay RL. Comparison of cannabidiol, antioxidants, and diuretics in reversing binge ethanol-induced neurotoxicity. J. Pharmacol. Exp. Ther. 2005; 314(2): 780–788.
- Mukhopadhyay P, Rajesh M, Horváth B, Bátkai S, Park O, Tanchian G, Gao RY, Patel V, Wink DA, Liaudet L, Haskó G, Mechoulam R, Pacher P. Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic. Biol. Med. 2011;50(10):1368–1381.
- Zhornitsky S1, Potvin S. Cannabidiol in humans-the quest for therapeutic targets.Pharmaceuticals (Basel).2012 May 21;5(5):529-52.
- Zuardi AW, Hallak JE, Crippa JA. Interaction between cannabidiol (CBD) and (9)- tetrahydrocannabinol (THC): influence of administration interval and dose ratio between the cannabinoids. Psychopharmacology (Berl). 2012;219(1): 247-49.
- Smith LA, Azariah F, Lavender VT, Stoner NS, Bettiol S. Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy.Cochrane Database Syst Rev. [Internet] 2015[cited 2018 March 13]. . Available from:http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009464.pub2/abstract;jsessionid=7318D0F0E1D930E61BAC5FE7FA4EC7BC.f03t04
- Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, KeurentjesJC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. 2015 Jun 23-30;313(24):2456-73.
- Blumentrath CG, Dohrmann B, Ewald N. Cannabinoid hyperemesis and the cyclic vomiting syndrome in adults: recognition, diagnosis, acute and long-term treatment.Ger Med Sci.2017;15:Doc06.
- Aviram J, Samuelly-Leichtag G. Efficacy of Cannabis-Based Medicines for Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain Physician.2017;20(6):E755-96.
- Häuser W, Petzke F, Fitzcharles MA. Efficacy, tolerability and safety of cannabis-based medicines for chronicpain management – An overview of systematic reviews.Eur J Pain.2018 Mar;22(3):455-70.
- Moulin, D., Boulanger, A., Clark, A.J., Clarke, H., Dao, T. et al.Pharmacological management of chronic neuropathic pain: Revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014; 19, 328–35.
- Ottawa (ON): Canadian Agency for Drugs and Technologies in Health. Cannabinoid Buccal Spray for Chronic Non-Cancer or Neuropathic Pain: A Review of Clinical Effectiveness, Safety, and Guidelines [Internet]. 2016 [cited 2018 March 13]. Available from: https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0089684/
- I Tomida, RG Pertwee, A Azuara-Blanco. Cannabinoids and glaucoma. Br J Ophthalmol. 2004;88(5): 708-13.
- Tomida, I, Azuara-Blanco A, House H, Flint M, Pertwee RG, Robson PJ. Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. J.Glaucoma. 2006; 15(5): 349-53.
- Nielsen S, Germanos R, Weier M, Pollard J, Degenhardt L, Hall W, Buckley N, Farrell M. The Use of Cannabis and Cannabinoids in Treating Symptomsof Multiple Sclerosis: a Systematic Review of Reviews. CurrNeurolNeurosci Rep. 2018 Feb 13;18(2):8.
- Collin C, Ehler E, Waberzinek G, Alsindi Z, Davies P, Powell K,et al. A double-blind, randomized, placebo-controlled, parallelgroupstudy of Sativex, in subjects with symptoms of spasticitydue to multiple sclerosis. Neurol Res. 2010;32(5):451–9.
- D’Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu YT, Braley G, Gueorguieva R, Krystal JH. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology. 2004 Aug; 29 (8): 1558–1572.
- Crippa JA, Zuardi AW, Garrido GE, Wichert-Ana L, Guarnieri R, Ferrari L, Azevedo-Marques PM, Hallak JE, McGuire PK, Filho Busatto G. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology 2004 Feb;29(2):417-26.
- Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Rev Bras Psiquiatr. 2008; 30: 271–280.
- Viveros MP, Llorente R, Moreno E, Marco EM. Behavioural and neuroendocrine effects of cannabinoids in critical developmental periods. BehavPharmacol 2005, 16:353-62.
- Bergamaschi MM1, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R, Hallak JE, Zuardi AW, Crippa JA. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. 2011 May;36(6):1219-26.
- Bhattacharyya S, Morrison PD, Fusar-Poli P. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010, 35:764-74.
- Hausman-Kedem M, Kramer U. Efficacy of medical cannabis for treatment of refractory epilepsy in children and adolescents with emphasis on the Israeli experience. Isr Med Assoc J.2017;19:76-8.
- Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S. Cannabidiol in Dravet Syndrome Study Group. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med.2017 May 25;376(21):2011-20.
- Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K; GWPCARE4 Study Group. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. 2018 Jan 25. pii: S0140-6736(18)30136-3.
- Roitman P, Mechoulam R, Cooper-Kazaz R, Shalev A: Preliminary, open-label, pilot study of add-on oral Delta9- tetrahydrocannabinol in chronic post-traumatic stress disorder. Clin Drug Investig. 2014, 34:587-91
- Huestis MA. Human cannabinoid pharmacokinetics. Chem.Biodivers. 2007; 4(8): 1770-804.
- Valeant Canada. Cesamet Product Monograph.
- GW Pharmaceuticals. Sativex Product Monograph. 2015.
- GBD 2015 Tobacco Collaborators. Smoking prevalence and attributable disease burden in 195 countries and territories, 1990–2015: a systematic analysis from the Global Burden of Disease Study 2015. Lancet. 2017; 389(10082):1885-906
- Braude, M.C. Toxicology of cannabinoids In Cannabis and its Derivatives, M.Paaton and J.Crown, eds, pp 89-99. Oxford: Oxford University Press, 1972;
- Chan PC, Sills RC, Braun AG, Haseman JK, Bucher JR. Toxicity and carcinogenicity of delta 9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice. 1996; 30(1):109-117.
- Tai S, Fantegrossi WE. Pharmacological and Toxicological Effects of Synthetic Cannabinoids and Their Metabolites.Curr Top BehavNeurosci. 2017;32:249-262.
- Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. Abstinence symptoms following oral THC administration to humans. 1999; 141:385–394.
- Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. Abstinence symptoms following smoked marijuana in humans. 1999; 141:395–404.
- Joy JE, Watson SJ, Benson JA. First, do no harm: consequences of marijuana use and abuse. Marijuana and medicine: Assessing the science base. Institute of Medicine. Washington, DC: National Academy Press, 1999.
- De Vry J, Jentzsch KR, Kuhl E, Eckel G. Behavioral effects of cannabinoids show differential sensitivity to cannabinoid receptor blockade and tolerance development. Behav.Pharmacol. 2004;15(1): 1-12.
- Rog DJ, Nurmikko TJ, Young CA. Oromucosal delta9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin.Ther. 2007;.29(9): 2068-79.
- Serpell M G, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J.Neurol. 2012;260(1): 285-95.
- Vandrey R. Haney M. Pharmacotherapy for cannabis dependence: how close are we? CNS.Drugs. 2009;23(7): 543-53.
- Reiman A, Welty M, Solomon P. Cannabis as a substitute for Opioid-Based Pain Medication: PatientSelf-Report.Cannabis Cannabinoid Res. 2017;2(1):160-6.
- Zuurman L, Ippel AE, Moin E, van Gerven JM. Biomarkers for the effects of cannabis and THC in healthy volunteers. 2009;67(1): 5-21.
- Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids [internet] Health Canada 2013 [cited 2018 March 13]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/medical-use-marijuana/information-medical-practitioners/information-health-care-professionals-cannabis-marihuana-marijuana-cannabinoids.html#chp80
- Colizzi M, Bhattacharyya S. Does Cannabis Composition Matter? Differential Effects of Delta-9-tetrahydrocannabinol and Cannabidiol on Human Cognition. Curr Addict Rep.2017;4(2):62-74.
- Osborne AL, Solowij N, Weston-Green K. A systematic review of the effect of cannabidiol on cognitive function: Relevance to schizophrenia. NeurosciBiobehav Rev.2017;72:310-324.
- Volkow ND, Baler RD, Compton WM, Weiss SR.Adverse Health Effects of Cannabis Use. N Engl J Med. 2014 Jun 5;370(23):2219-277.
- Koenders L, Lorenzetti V, de Haan L, Suo C, Vingerhoets W, van den Brink W, Wier RW, Meijer CJ, Machielsen M, Goudriaan AE, Veltman DJ, Yücel M, Cousijn J. Longitudinal study of hippocampal volumes in heavy cannabis users. J Psychopharmacol.2017; 31(8):1027-1034.
- Levine A, Clemenza K, Rynn M, Lieberman J.Evidence for the Risks and Consequences of Adolescent Cannabis Exposure.J Am Acad Child Adolesc Psychiatry.2017;56(3):214-225.
- The College of Physicians and Surgeons of Ontario. [internet] Marijuana for medical purposes. updated December 2016 [cited 2018 March 13]. Available from:http://www.cpso.on.ca/policies-publications/policy/marijuana-for-medical-purposes
- Favrat B, Menetrey A, Augsburger M, Rothuizen LE, Appenzeller M, Buclin T, Pin M, Mangin P, Giroud C. Two cases of “cannabis acute psychosis” following the administration of oral cannabis. BMCPsychiatry. 2005;5: 17-22.
- McGuire P, Robson P, Cubala WJ, Vasile D, Morrison PD, Barron R, Taylor A, Wright S.Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial.Am J Psychiatry.2017; appiajp201717030325.
- Radhakrishnan R, Wilkinson ST, D’Souza DC. Gone to Pot – A Review of the Association between Cannabis and Psychosis. Front Psychiatry.2014;5:54.
- Rohleder C, Müller JK, Lange B, Leweke FM. Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence.Front Pharmacol.2016;7:422.
- Turna J, Patterson B, Van Ameringen M. Is cannabis treatment for anxiety, mood, and related disorders ready for prime time? Depress Anxiety.2017;34(11):1006-1017.
- Health Canada. Authorized Licensed Producers of Cannabis for Medical Purposes. [internet] 2018 [cited 2018 March 13]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/medical-use-marijuana/licensed-producers/authorized-licensed-producers-medical-purposes.html
- Health Canada. Hemp and the hemp industry Frequently Asked Questions. [internet] 2017 [cited 2018 March 13]. Available from: https://www.canada.ca/en/health-canada/services/health-concerns/controlled-substances-precursor-chemicals/industrial-hemp/about-hemp-canada-hemp-industry/frequently-asked-questions.html#a1