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Cannabis-derived pharmaceuticals.

INTRODUCTION

Cannabis, commonly known as marijuana, weed or pot, is a natural product derived from the Cannabis sativa plant. It has been used medicinally for thousands of years in China, India, The Middle East and in the West through much of the 19th century. (1,2) Anecdotally, and in the medical literature, Cannabis has been recommended as a treatment for numerous diseases including pain, arthritis, glaucoma, neurological disorders including epilepsy, multiple sclerosis (MS) and Parkinson's disease and diabetes and a variety of ailments including loss of appetite, anxiety, nausea and vomiting and menstrual cramps. (3,4)

The plethora of therapeutic benefits offered by Cannabis has largely been attributed to a class of naturally-occurring, plant-derived terpenophenolic compounds known as phytocannabinoids. (5,6) Inhalation (smoking and vaporization) and ingestion are the most common routes of administration of Cannabis products but other routes including rectal, sublingual, transdermal, ophthalmic, intrathecal and intravenous routes have been used. (7)

In addition to the phytocannabinoids, endogenous or endocannabinoids that are produced by the body have been identified and characterized. Endocannabinoids are thought to modulate or play a regulatory role in a variety of physiological processing including appetite, pain-sensation, mood, memory, inflammation, insulin sensitivity and fat and energy metabolism. (8,9) Finally, a number of synthetic cannabinoids (mimetics of naturally-occurring endocannabinoids) have been developed to better understand cannabinoid receptor biology/function/selectivity and, also, as possible treatments for a variety of therapeutic indications including pain management, inflammation, cancer and neurodegenerative diseases. (9)

MECHANISM OF ACTION

Cannabinoids (endogenous, synthetic and phytocannabinoids) are thought to exert their physiological effects by interacting with CB1 and CB2, G-coupled protein cannabinoid receptors that are widely distributed and found throughout the body. (10-13)

CB1 receptors which constitute the most prevalent neurotransmitter system in the brain and central nervous systems (CNS) are primarily found in basal ganglia, hippocampus and cerebellum. (10,11) In contrast, CB2 receptors are found almost exclusively on cells of the immune system including T and B cells and mainly appear in tissues when there is cellular pathology. CB1 receptors are thought to be involved in the effects of Cannabis on appetite, mood motor function and neurocognition (12,14) whereas CB2 receptors appear to be responsible for mediating the anti-inflammatory and analgesic effects of Cannabis. (15-18)

Recent studies showed that certain cannabinoids such as CBD interact with the transient receptor potential vanilloid channels of the endovanilloid system, e.g, capsaicin receptors that are thought to modulate neuropathic pain and were recently shown to be involved in bone growth. (19-21) Also, other studies suggest that cannabinoids may exert therapeutic their effects by targeting [alpha]3 glycine receptors, stimulating PPAR[gamma] receptor activity, increasing intracellular [Ca.sup.2] and antagonizing GPR55 receptors. (22,23) The mechanisms of action of cannabinoids for a variety of clinical indications including chronic pain, cancer, and multiple sclerosis (MS) has been extensively reviewed elsewhere. (5,17,24,25,26-29)

PHARMACOLOGICALLY-ACTIVE PHYTOCANNABINOIDS

To date, over 60 cannabinoids unique to Cannabis have been identified, including the most psychoactive cannabinoid, [DELTA]-9-tetrahydrocannabinol commonly referred to as THC. Other medically- relevant and well characterized cannabinoids include; [DELTA]-9-tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC) cannabinol (CBN) and cannabidivarin (CBDV); with THC, CBD and CBN being the most abundant phytocannabinoids (Table 1). (30)

THC is the main active cannabinoid in Cannabis and is primarily responsible for its psychoactive properties. It was the first cannabinoid to be isolated and identified (1964) in Cannabis resin and flowers. (31) The concentration of THC found in Cannabis and its extracts can vary based on plant variety, cultivation techniques and type of preparation. Pure THC can be derived from natural sources (extraction from cannabis plants) or produced synthetically. (32) The molecule acts as a partial agonist of CB1 receptors found in the CNS and CB2 receptors found on immune cells. (32)

While THC exhibits potent anti-inflammatory and anti-emetic properties, its development as a therapeutic drug treatment has been hindered by its accompanying psychotropic effects. Nevertheless, in the past, dronabinol (Marinol[TM]) a synthetic THC and nabilone (Cesamet[TM]) a synthetic THC-mimetic received FDA approval as appetite stimulants and treatments for chemotherapy induced nausea and vomiting (CINV). (7) However, neither drug is widely prescribed. Finally, possible development of tolerance to THC could limit the long term clinical and therapeutic uses of the molecule.

[DELTA]-9-tetrahydrocannabivarin (THCV) is a relatively abundant non-psychoactive phytocannabinoid present in Cannabis. (33) THCV is a CB1 receptor antagonist and a partial agonist for CB2 receptors. Several studies showed that THCV has anti-convulsive effects in animal models and that it may be useful as a treatment for epilepsy and other CNS diseases. (33-35)

Cannabidiol (CBD) is the major non-psychotropic cannabinoid found in Cannabis. It has been found to possess anti-epileptic, anti-inflammatory, anti-emetic, muscle relaxing, anxiolytic, neuroprotective and antipsychotic activity and reduces the psychoactive effects of THC. (36,22,23) Unlike THC, the mode of action of CBD is not fully understood and it is thought to act via nonCB1 receptor mechanisms because it has low affinity for CB1 and CB2 receptors. (35) Recent studies suggest that CBD may exert its action by targeting [alpha]3 glycine receptors, stimulating PPAR[gamma] receptor activity, increasing intracellular [Ca.sup.2] and antagonizing GPR55 receptors. (22,23) Other studies suggest that CBD may be a CB1 receptor antagonist (37) and may also exerts its effects by stimulating the vanilloid receptor type 1 (VR1) with efficacy similar to that of capsaicin. (20,21,38) Also, CBD is thought to inhibit the degradation of the endocannabinoid anandamide (38) and may interfere with THC metabolism. (39) CBD is being evaluated as a possible treatment for epilepsy (40), schizophrenia (41) and for its anti-tumorigenic effects. (42)

Cannabigerol (CBG) is another non-psychoactive phytocannabinoid found in Cannabis and the chemical precursor of THC and CBD. CBG has been reported to relieve intraocular pressure and possesses anti-inflammatory properties. (43-45) The molecule has also been reported to have anti-convulsive effects but these effects have yet to be substantiated. (46) CBG is being evaluated as a possible treatment for multiple sclerosis and inflammatory bowel disease. (45,47)

Another non-psychoactive cannabinoid found in Cannabis with possible therapeutic benefits is cannabichromene (CBC). CBC is thought to possess analgesic and anti-inflammatory activity. (48,49) Other studies suggest that CBC may also possess some neuroprotective effects. (34,49)

Cannabidivarin (CBDV) is a non-psychotropic homolog of CBD. CBDV is actively being developed as a therapeutic to treat epilepsy and convulsions because of its previously observed anti-convulsive and anti-epileptic activities in animal models. (34,35,50) CBDV has been reported to act via CB2 cannabinoid receptors-dependent mechanisms but direct CB2 receptor binding has yet to be demonstrated. (50,51)

Cannabinol (CBN) is a weak psychoactive cannabinoid found only in trace amounts in Cannabis (52) It is mostly a degradation product (metabolite) of THC. (53) Studies suggest that CBN acts as a weak agonist of CB1 receptors and has a higher affinity for CB2 receptors albeit lower than the affinity of THC for CB2 receptors. (54,55) Because CBN is a partially-selective agonist of CB2 receptors it may possess possible anti-inflammatory and immunosuppressant therapeutic effects.

CLINICAL EFFECTS

Over the past decade, despite a challenging legal and regulatory landscape, a surprising number of clinical studies have been conducted with Cannabis and cannabinoids for a variety of therapeutic indications. (7,28,56,57) The main areas of clinical research include chronic non-cancer pain, neurological diseases including MS and epilepsy, (28,29,57,58) and oncology including analgesia, anorexia, chemotherapy-induced nausea and vomiting (CINV). (5,7,27,42,59)

A systematic review of 18 randomized controlled clinical trials for chronic non-cancer pain conducted since 2003 revealed that smoked cannabis, cannabis extracts (oromucosal spray) and orally-administered synthetic THC (nabilone and dronabinol) had modest analgesic effects (compared with placebo) on 766 participants with chronic, neuropathic or acute non-cancer pain. (57) The databases that were searched to conduct this retrospective study included PubMed, Em base, CINAHL (EBSCO, PsycInfo, The Cochrane Library (Wiley) ISI Web of Science, ABI Inform (Proquest), Academic Search Premier, Clinical Trials.gov , Trials Central.org and clinical trial sites for Eli Lilly, GlaxoSmithKline, OALster (OCLCC) and Google Scholar. (46) However, the small number of participants, short trial durations and modest efficacy caused the authors to suggest that additional clinical trials will be necessary to conclusively determine the effects of cannabinoids on chronic pain management. To that end, there are currently 11 latestage US clinical trials in progress to assess the effects of smoked/ vaporized Cannabis (6) and cannabis extracts (6) on neuropathic and chronic pain (Table 3). However, it is important to note, that GW Pharma's Sativex[R] a cannabis extract containing 1:1 ratios of THC: CBD (that is delivered via oromucosal spray) has been approved outside the US as a treatment for chronic neuropathic and cancer-related pain. (60,61)

The immunomodulatory properties of cannabinoids suggested that they might be therapeutically useful in MS which is generally believed to be an autoimmune neurological disease. Based on a search of the PubMed database, 37 controlled clinical trials involving 1300 patients were conducted from 2005 to 2009 to assess the effects of Cannabis, cannabis extracts and synthetic THC on MS and MS-related muscle spasticity and pain. (56) The results of these studies showed that cannabis extracts containing different ratios of THC and CBD (Cannador[R] 2:1 and Sativex[R] 1;1), as well as THC and nabilone can improve MS-related symptoms of spasticity, pain and urinary incontinence. (56) Additional clinical studies led to the approval of Sativex[R] in 27 countries (not the US) as a treatment for MS spasticity. (58) At present, in the US, there are 15 late stage clinical trials in progress that are evaluating smoked/vaporized cannabis (2) and Sativex[R] (13) as treatments for MS and MS-related spasticity, pain and urinary incontinence (Table 3).

More recently, there have been reports that cannabis extracts with high concentrations of CBD may be effective anti-convulsants for children suffering from severe forms of uncontrollable epilepsy known as Dravet Syndrome and Lennox-Gastaut. (40,62) Four, early randomized, placebo-controlled clinical studies conducted between 1978-1990 involving 48 patients with epilepsy found that daily treatment with 200-300 mg of CBD for up to 4 months was safe and well tolerated. (52) The databases that were searched to conduct the study included the Cochrane Epilepsy Group Specialized Register (9 September 2013), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 8), MEDLINE (Ovid) (9 September 2013), ISI Web of Knowledge (9 September 2013), CINAHL (EBSCOhost) (9 September 2013), and ClinicalTrials. gov (9 September 2013). However the small number of patients and short trial duration were not sufficient to draw any conclusions about CBD's efficacy. (63) More recently, GW pharma's Epidiolex, a liquid formulation of highly purified Cannabis-derived CBD was granted Orphan Drug Designation by FDA as a treatment for Dravet and Lennox-Gastaut syndromes and other pediatric epilepsy syndrome. (64) Currently, there are 7 mid to late stage clinical trials underway to evaluated Epidiolex's anti-epileptic properties (Table 3).

In the 1970s, purified and synthetic cannabinoids were being evaluated as palliative treatments for cancer related symptoms. (65) This led to the early approval of dronabinol and nabilone as treatments for CINV but their use has not been extended to treat cancer-related pain or wasting (although dronabinol is approved in the US as an appetite stimulant for patients with weight loss from HIV/AIDS). Interestingly, inhaled Cannabis, and extracts containing THC and CBD have been clinically found to be more effective in treating cancer-related neuropathic pain than placebo (66) but their effectiveness compared with conventional pain medications is uncertain. (7) Nevertheless, Sativex[R] is an approved treatment for cancer-related pain in 27 countries outside of the US. Four clinical trials are underway in the US to determine the effects on Sativex[R] on advanced cancer pain and chemotherapy induced neuropathic pain (Table 3).

One of the earliest recognized clinical indications for cannabinoids was CINV. A 1988 prospective open label trial found that inhaled cannabis effectively controlled nausea and vomiting in 78% of 56 patients who had inadequate control of nausea and vomiting with conventional anti-emetics. (7) Also, a later report that evaluated 30 trials and over 1300 participants determined that nabilone and dronabinol were more effective than conventional anti-emetics in controlling acute CINV. (67)

There is a growing body of evidence that cannabinoids exhibit anti-tumor and cancer--fighting effects. (7,57) Numerous studies have demonstrated inhibition of tumor growth in vitro and in a variety of animal models of disease for cancer including glioblastoma, breast, prostate, thyroid, colon, skin, pancreatic, leukemia and lymphoma. (68) The exact mechanism by which cannabinoids exert their anti-tumor effects is thought to occur via suppression of proliferative cell signaling pathways, inhibition of angiogenesis (blood vessel formation) and cell migration, stimulation of apoptosis (programmed cell death) and induction of autophagy (intracellular degradation). (68,69) Interestingly, cannabinoid receptors CB1 and CB2 have been found in higher concentrations on tumor cells than on surrounding normal tissue for a variety of cancers. (70,71) Also, several studies suggest that cannabinoids may selectively inhibit tumor cell growth and proliferation while sparing normal tissue. (59,68) Although cannabinoids exhibit possible anti-tumor effects, only a single Phase 1 clinical trial that assessed the safety and efficacy of THC in 9 patients with treatment refractory glioblastoma mutliforme has been published. (65) However, at present, there are two (2) Phase 2 clinical trials underway (Table 3) to assess the effect of cannabis extracts on solid tumor growth (CBD) and glioblastoma (Sativex[R]).

Finally, there are a number of mid to late clinical trials underway in the US to assess the effects of cannabis extracts and cannabinoids on other therapeutic indications including Huntington's Disease, ulcerative colitis, Crohn's disease, schizophrenia and graft vs. host disease (Table 3).

COMMERCIALIZING CANNABIS-DERIVED PRODUCTS

The current regulatory and legal environments for Cannabis-derived products is extremely difficult and fraught with numerous challenges. For example, in the US, Cannabis and products derived from it (including hemp) are federally classified as Schedule I drugs according to the US Controlled Substances Act. This means that Cannabis and its products have been deemed to have "no currently accepted medical use in treatment in the US" (heroin and LSD are also schedule I drugs), are harmful and consequently, are illegal. Not surprisingly, its Schedule 1 classification has seriously hindered Cannabis research in the US and made it extremely challenging for drug companies developing Cannabis-derived pharmaceutical products. However, over the past decade or so, 34 states including the District of Columbia have enacted legislation that permits some form of Cannabis consumption for medical purposes. Yet, despite this, Cannabis and products derived from it remain illegal at the federal level and interstate transport (even between states where medical marijuana has been legalized) is illegal and criminally punishable.

The confusion regarding Cannabis use at the state and federal levels has given rise to two distinct types of companies that are attempting to commercialize Cannabis and products derived from it. The first of these are commonly referred to as medical marijuana or medical Cannabis companies. Typically, products from these companies are botanical extracts or actual plant materials derived from specific Cannabis strains with anecdotally-reported medicinal properties that can be topically applied, ingested, smoked or vaporized. Patients require a "prescription" from a state-licensed physician to obtain medical marijuana and it can only be used in states that permit consumption of Cannabis for medical purposes. It is important to note, that while a prescription is required for medical Cannabis use, these products do not require human clinical testing for safety, tolerability and efficacy (like other prescription drugs) prior to their sale in states where medical marijuana is legal.

In contrast with medical marijuana companies, biopharmaceutical companies including GW Pharma, Kannalife, Aphios and others (Table 1) are committed to developing Cannabis-derived pharmaceuticals using conventional US Food and Drug Administration regulatory approval pathways. UK-based GW Pharma is the clear leader in Cannabis-derived pharmaceutical space--its flagship product Sativex[R], a plant extract, has been approved as a treatment for cancer-related pain and MS spasticity in 27 countries outside the US. In April 2014, FDA granted Sativex[R] Fast Track designation for the treatment of pain in patients with advanced cancer who experience inadequate analgesia during optimized chronic opioid therapy. (64) Sativex[R] is currently in US Phase 3 clinical trials for this indication (Table 3). Most of the other companies developing Cannabis-derived pharmaceuticals (extracts or individual cannabinoids) are in pre-clinical development or very early stage clinical trials (Table 2).

REGULATORY AND COMMERCIALIZATION HURDLES

While the business case for developing pharmaceutical Cannabis-derived products is a sound one, the time and costs associated with commercializing these products is certain to be greater than those associated with medical marijuana. This is because medical marijuana can be prescribed and sold in states (where it is legal) without scientific review or human clinical testing. And, while FDA has signaled a willingness to review new drug applications for Cannabis-derived pharmaceuticals, the agency has yet to issue definitive guidance for regulatory approval of these products. Consequently, the actual costs, regulatory requirements and time required for FDA approval for Cannabis-derived products are difficult to gauge at the present time. Nevertheless, garnering FDA approval for Cannabis-derived pharmaceuticals may offer several competitive advantages as compared with medical marijuana products that currently dominate the US market.

First, the average cost per patient of Sativex[R] to treat MS spasticity in countries where it is approved has been estimated to be roughly $16,000. (72) Several studies have suggested, (72,73) that the high price of Sativex[R] will make it unlikely to be considered cost effective by regulators in countries with government-mandated national formularies like the UK, Ireland and Australia. However, this should not be an impediment for the US market because the US federal government does not set drug prices nor determines formulary placement. Moreover, medical marijuana is currently an out-of-pocket expense for patients whereas newly FDA approved Cannabis-derived products are likely to be reimbursed at rates similar to those of synthetic cannabinoids such as dronabinol and nabilone.

Second, unlike medical marijuana (which as previously stated is a Schedule 1 drug), FDA approved Cannabis-based pharmaceuticals like dronabinol and nabilone have been classified or reclassified as Schedule 2 (opioids) or Schedule 3 (codeine) drugs. Federal regulators are likely to apply the same scheduling criteria to the next generation of FDA-approved Cannabis-derived pharmaceuticals like Sativex[R] and others. Rescheduling will effectively allow these products to compete with medical marijuana because unlike medical marijuana--which is legal in certain states and cannot be transported across state borders because of Federal law--FDA-approved Cannabis-derived pharmaceuticals can be legally prescribed, sold and used in all 50 US states and US territories.

Finally, and perhaps most importantly, physicians may be inclined to prescribe FDA-approved Cannabis drugs rather than medical marijuana because the approved products have been medically evaluated in human clinical trials and officially deemed to be safe, effective treatments for specific clinical indications. In contrast, questions or suspicions regarding medical marijuana's safety, effectiveness and quality are likely to linger until industry best practices are clearly established and adopted.

MEDICAL AND TECHNICAL CHALLENGES

In addition to legal and regulatory challenges, there are technical and manufacturing issues that must also be addressed before Cannabis-derived pharmaceuticals can be successfully commercialized. First, substantial financial investment in infrastructure, equipment and production facilities will be required to breed and grow different Cannabis strains to obtain appropriate chemical compositions and extracts to treat specific therapeutic indications. Industry experts contend that this investment must include research on strain construction, cannabinoid concentrations at different stages of plant growth/harvest times and yield improvements. Also, included in infrastructure costs is applying Current Good Manufacturing Practices (CGMPs) to plant growth, extraction processes, formulation and manufacture of Cannabis-derived pharmaceuticals which will guarantee product safety, efficacy and quality. Interestingly, crop failure (not having a redundancy of supply) is a serious issue that all commercial entities in the medical Cannabis industry must address and contend with to meet commercial demand.

Second, the route of delivery and dosing regimens for Cannabis-based pharmaceuticals for specific indications will be vitally important. While smoking/vaporizing Cannabis is currently the most obvious method to deliver desired therapeutic effects, (7) it may not be the most effective to maximize its therapeutic benefits for different indications and individual patients. Over the past few years, there has been a growing interest in exploring oral, oromucosal, topical and sustained release delivery of Cannabis-derived pharmaceutical depending upon the therapeutic indication of interest. (74,75)

Finally, safeguards must be put into place to ensure protection against misuse, fraud and abuse of Cannabis-derived pharmaceuticals by healthcare providers and patients. The development of novel metered dose devices to deliver these products will help to limit misuse and abuse.

A WAY FORWARD?

Surveys conducted in the 1990s (76) and 2000s (77) found that between 30% and 54% of internists and oncologists were interested in offering cannabis as a therapeutic option for their patients. Yet, despite this, the surveys showed that many physicians were concerned about the legality of making medical cannabis recommendations or writing prescriptions regardless of state laws. (7) Also, the existing confusion about the legality/criminality of Cannabis-derived products is certain to have an effect on the behavior of insurers and third party payers. At this point, it is not clear whether or not payers will place Cannabis-derived pharmaceuticals on their formularies and reimburse patients who use them. Alternatively, it is possible that insurers may reimburse patients who use FDA-approved Cannabis products but continue to treat medical marijuana as an out-of-pocket expense for patients who use it.

The legal patchwork for Cannabis that has evolved over time in the US suggests that Cannabis-derived products may only be available in the states that have legalized their use. Consequently, companies developing Cannabis-based pharmaceuticals may have to duplicate commercial operations in states where medical Cannabis is legal and underwrite multiple product launches in individual states because interstate transport of these products is illegal. This would be extremely costly (driving up product prices) and also decrease patient access to products that address unmet medical needs. To that point, most companies developing Cannabis-derived pharmaceuticals believe that rescheduling of these products from Schedule 1 drugs to Schedule 2 or 3 would obviate these concerns. Others contend that legalization at the federal level will be necessary for the US Cannabis market to grow to its full potential.

Finally, because Cannabis-derived pharmaceuticals represent a new class of therapeutics, patient and healthcare provider education will be vital to successfully commercialize them. Put simply, if physicians don't understand Cannabis-derived pharmaceuticals and are not convinced of product safety and efficacy, then, they will be reluctant to write prescriptions for these products. Nevertheless, the burgeoning popular demand for medical marijuana suggests that commercializing Cannabis-derived pharmaceuticals will help to address rising unmet medical needs for a variety of life-altering clinical indications including cancer, neurological disorders and chronic pain.

Clifford S. Mintz is President and Founder of BioInsights Inc.

Evan Nison is Director of the East Coast Cannabis Division of Terra Tech Corp.

AJ Fabrizio is Director of Research at Terra Tech Corp.

Correspondence:

Clifford S. Mintz, BioInsights, Inc, US. Email1: cliffmz@ yahoo.com

REFERENCES

(1.) Russo, E.B. (2007) History of cannabis and its preparations in saga, science, and sobriquet. Chemistry & biodiversity 4(8): 1614-1648.

(2.) Schultes, R.E. HA. (1992) Plants of the gods: their sacred, healing and hallucinogenic powers. Rochester, New York: Healing Arts Press.

(3.) Iversen, L. (2000) The science of marijuana. Oxford, England: Oxford University Press.

(4.) Corey, S. (2005) Recent developments in the therapeutic potential of cannabinoids. Puerto Rico health sciences journal 24(1): 19-26.

(5.) Alexander, A., Smith, P.F., & Rosengren, R.J. (2009) Cannabinoids in the treatment of cancer. Cancer letters 285(1): 6-12.

(6.) Aizpurua-Olaizola, O., Omar, J., Navarro, P., Olivares, M., Etxebarria, N., & Usobiaga, A. (2014) Identification and quantification of cannabinoids in Cannabis sativa L. plants by high performance liquid chromatography-mass spectrometry. Analytical and bioanalytical chemistry 406(29): 7549-7560.

(7.) Bowles, D.W., O'Bryant, C.L., Camidge, D.R., & Jimeno, A. (2012) The intersection between cannabis and cancer in the United States. Critical reviews in oncology/ hematology 83(1): 1-10.

(8.) Pacher, P., Batkai, S., & Kunos, G. (2006) The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological reviews 58(3): 389-462.

(9.) Pacher, P., & Kunos, G. (2013) Modulating the endocannabinoid system in human health and disease-successes and failures. The FEBS journal 280(9): 1918-1943.

(10.) Elphick, M.R., & Egertova, M. (2001) The neurobiology and evolution of cannabinoid signaling. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 356(1407): 381-408.

(11.) Grotenhermen, F. (2005) Cannabinoids. Current drug targets. CNS and neurological disorders 4(5): 507-530.

(12.) Matsuda, L.A., Lolait, S.J., Brownstein, M.J., Young, A.C., & Bonner, T.I. (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346(6284): 561-564.

(13.) Bosier, B., Muccioli, G.G., Hermans, E., & Lambert, D.M. (2010) Functionally selective cannabinoid receptor signalling: therapeutic implications and opportunities. Biochemical pharmacology 80(1): 1-12.

(14.) Hill, A.J., Mercier, M.S., & Hill, T.D., et al. (2012) Cannabidivarin is anticonvulsant in mouse and rat. British journal of pharmacology 167(8): 1629-1642.

(15.) Guindon, J., & Hohmann, A.G. (Jan 2008) Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. British journal of pharmacology 153(2): 319-334.

(16.) Fernandez-Ruiz, J., Pazos, M.R., Garcia-Arencibia, M., Sagredo, O., Ramos, J.A. (2008) Role of CB2 receptors in neuroprotective effects of cannabinoids. Molecular and cellular endocrinology 286(1-2 Suppl 1): S91-S96.

(17.) Anand, P., Whiteside, G., Fowler, C.J., & Hohmann A.G. (2009) Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain research reviews 60(1): 255-266.

(18.) Pertwee, R.G., & Ross, R.A. (2002) Cannabinoid receptors and their ligands. Prostaglandins, leukotrienes, and essential fatty acids 66(2-3): 101-121.

(19.) Rahn, E.J., & Hohmann, A.G. (2009) Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics 6(4): 713-737.

(20.) De Petrocellis, L., Orlando, P., Schiano Moriello, A., Aviello, G., Stott, C., Izzo, A.A., & Di Marzo, V. (2012) Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. ACTA Physiologica 204: 255-266.

(21.) Qin, N., Neeper, M.P., Liu, Y., Hutchinson, T.L., Lubin, M.L., Flores, C.M. (2008) TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. The Journal of neuroscience: the official journal of the Society for Neuroscience 28(24): 6231-6238.

(22.) Campos, A.C., Moreira, F.A., Gomes, F.V., Del Bel, E.A., & Guimaraes, F.S. (2012) Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 367(1607): 3364-3378.

(23.) Xiong, W., Cui, T., & Cheng, K., et al. (2012) Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha3 glycine receptors. The Journal of experimental medicine 209(6): 1121-1134.

(24.) Beaulieu, P., & Ware, M. (2007) Reassessment of the role of cannabinoids in the management of pain. Current opinion in anaesthesiology 20(5): 473-477.

(25.) Bhattacharyya, S., Atakan, Z., Martin-Santos, R., Crippa, J.A., & McGuire, P.K. (2012) Neural mechanisms for the cannabinoid modulation of cognition and affect in man: a critical review of neuroimaging studies. Current pharmaceutical design 18(32): 5045-5054.

(26.) Boychuk, D.G., Goddard, G., Mauro, G., & Orellana, M.F. (Winter 2015) The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. Journal of oral & facial pain and headache 29(1): 7-14.

(27.) Chakravarti, B., Ravi, J., & Ganju, R.K. (2014) Cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget 5(15): 5852-5872.

(28.) Giacoppo, S., Mandolino, G., Galuppo, M., Bramanti, P., & Mazzon, E. (2014) Cannabinoids: new promising agents in the treatment of neurological diseases. Molecules 19(11): 18781-18816.

(29.) Zajicek, J.P., & Apostu, V.I. (2011) Role of cannabinoids in multiple sclerosis. CNS drugs 25(3): 187-201.

(30.) Gerra, G., Zaimovic, A., & Gerra, M.L., et al. (2010) Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists. Recent patents on CNS drug discovery 5(1): 46-52.

(31.) Mechoulam, R., & Gaoni, Y.A. (1965) Total Synthesis of Dl-Delta-1-Tetrahydrocannabinol, the Active Constituent of Hashish. Journal of the American Chemical Society 87: 3273-3275.

(32.) F HAG. (2010) Review on clinical studies with cannabis and cannabinoids 2005-2009. Cannabinoids 5(special issue): 1-21.

(33.) Hill, A.J., Weston, S.E., Jones, N.A., et al. (2010) Delta(9)-Tetrahydrocannabivarin suppresses in vitro epileptiform and in vivo seizure activity in adult rats. Epilepsia 51(8): 1522-1532.

(34.) Hill, A.J. WC, Whalley, B.J., & Spehens, G.J. (2012) Phytocannabinoids as novel therapeutic agents in CNS disorders Pharmacology & therapeutics 133: 79-97.

(35.) Jones, N.A., Hill, A.J., & Smith, I., et al. (2010) Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. The Journal of pharmacology and experimental therapeutics 332(2): 569-577.

(36.) Russo, E., & Guy, G.W. (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Medical hypotheses 66(2): 234-246.

(37.) Zuardi, A.W., Shirakawa, I., Finkelfarb, E., & Karniol, I.G. (1982) Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology 76(3): 245-250.

(38.) Bisogno, T., Hanus, L., & De Petrocellis, L., 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. British journal of pharmacology 134(4): 845-852.

(39.) Bornheim, L.M., & Grillo, M.P. (1998) Characterization of cytochrome P450 3A inactivation by cannabidiol: possible involvement of cannabidiol-hydroxyquinone as a P450 inactivator. Chemical research in toxicology 11(10): 1209-1216.

(40.) Cilio, M.R., Thiele, E.A., & Devinsky, O. (Jun 2014) The case for assessing cannabidiol in epilepsy. Epilepsia 55(6): 787-790.

(41.) Deiana, S. (Jan 2013) Medical use of cannabis. Cannabidiol: a new light for schizophrenia? Drug testing and analysis 5(1): 46-51.

(42.) Cridge, B.J., & Rosengren, R.J. (2013) Critical appraisal of the potential use of cannabinoids in cancer management. Cancer management and research 5: 301-313.

(43.) Cascio, M.G., Gauson, L.A., Stevenson, L.A., Ross, R.A., & Pertwee, R.G. (2010) Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. British journal of pharmacology 159(1): 129-141.

(44.) Colasanti, B.K. (Winter 1990) A comparison of the ocular and central effects of delta 9-tetrahydrocannabinol and cannabigerol. Journal of ocular pharmacology 6(4): 259-269.

(45.) Borrelli, F., Fasolino, I., & Romano, B., et al. (2013) Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Biochemical pharmacology 85(9): 1306-1316.

(46.) Dos Santos, R.G., Hallak, J.E., Leite, J.P., Zuardi, A.W., & Crippa, J.A. (Dec 4 2014) Phytocannabinoids and epilepsy. Journal of clinical pharmacy and therapeutics.

(47.) Granja, A.G., Carrillo-Salinas, F., & Pagani, A., et al. (2012) A cannabigerol quinone alleviates neuroinflammation in a chronic model of multiple sclerosis. Journal of Neuroimmunepharmacology: the official journal of the Society on Neuroimmune Pharmacolog 7(4): 1002-1016.

(48.) Maione, S., Piscy. Decitelli, F., & Gatta, L., et al. (2011) Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action. British journal of pharmacology 162(3): 584-596.

(49.) Shinjyo, N., & Di Marzo, V. (2013) The effect of cannabichromene on adult neural stem/progenitor cells. Neurochemistry international 63(5): 432-437.

(50.) Amada, N., Yamasaki, Y., Williams, C.M., & Whalley, B.J. (2013) Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression. PeerJ 1: e214.

(51.) Scutt, A., & Williamson, E.M. (2007) Cannabinoids stimulate fibroblastic colony formation by bone marrow cells indirectly via CB2 receptors. Calcified tissue international 80(1): 50-59.

(52.) Karniol, I.G., Shirakawa, I., Takahashi, R.N., Knobel, E., & Musty, R.E. (1975) Effects of delta9tetrahydrocannabinol and cannabinol in man. Pharmacology 13(6): 502-512.

(53.) McCallum, N.D., Yagen, B., Levy, S., Mechoulam, R. (1975) Cannabinol: a rapidly formed metabolite of delta-1- and delta-6-tetrahydrocannabinol. Experientia 31(5): 520-521.

(54.) Mahadevan, A., Siegel, C., Martin, B.R., Abood, M.E., Beletskaya, I., & Razdan, R.K. (2000) Novel cannabinol probes for CB1 and CB2 cannabinoid receptors. Journal of medicinal chemistry 43(20): 3778-3785.

(55.) Petitet, F., Jeantaud, B., Reibaud, M., Imperato, A., & Dubroeucq, M.C. (1998) Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors. Life sciences 63(1): PL1-6.

(56.) Hazenkamp, A. G.F. (2010) Review on clinical studies with cannabis and cannabinoids 2005-2009. Cannabinoids 5(special issue): 1-21.

(57.) Lynch, M.E., & Campbell, F. (2011) Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. British journal of clinical pharmacology 72(5): 735-744.

(58.) Zajicek, J.P., Hobart, J.C., Slade, A., Barnes, D., Mattison, P.G., & Group, M.R. (2012) Multiple sclerosis and extract of cannabis: results of the MUSEC trial. Journal of neurology, neurosurgery, and psychiatry 83(11): 1125-1132.

(59.) Flygare, J., & Sander, B. (2008) The endocannabinoid system in cancer-potential therapeutic target? Seminars in cancer biology 18(3): 176-189.

(60.) Pharma, G. (2003) Cannabis-based medicines--GW pharmaceuticals: high CBD, high THC, medicinal cannabis--GW pharmaceuticals, THC: CBD. Drugs in R&D 4(5): 306-309.

(61.) Barnes, M.P. (2006) Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain. Expert opinion on pharmacotherapy 7(5): 607-615.

(62.) Maa, E., & Figi, P. (2014) The case for medical marijuana in epilepsy. Epilepsia 55(6): 783-786.

(63.) Gloss, D., & Vickrey, B. (2014) Cannabinoids for epilepsy. The Cochrane database of systematic reviews 3: CD009270.

(64.) Pharma, G. (2014) GW Pharmaceuticals announces that Sativex receives fast track designation from FDA in cancer pain. http://www.gwpharm.com/GW%20 Pharmaceuticals%20Announces%20that%20Sativex%20 Receives%20Fast%20Track%20Designation%20from%20 FDA%20in%20Cancer%20Pain.aspx. Accessed April 9, 2015.

(65.) Guzman, M., Duarte, M.J., & Blazquez, C., et al. (2006) A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. British journal of cancer 95(2): 197-203.

(66.) Notcutt, W., Price, M., & Miller, R., et al. (2004) Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 'N of 1' studies. Anaesthesia 59(5): 440-452.

(67.) Tramer, M.R., Carroll, D., Campbell, F.A., Reynolds, D.J., Moore, R.A., & McQuay, H.J. (2001) Cannabinoids for control of chemotherapy induced nausea and vomiting: quantitative systematic review. BMJ 323(7303): 16-21.

(68.) Pisanti, S., Malfitano, A.M., & Grimaldi, C., et al. (2009) Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents. Best practice & research. Clinical endocrinology & metabolism 23(1): 117-131.

(69.) Salazar, M., Carracedo, A., & Salanueva, I.J., et al. (2009) Cannabinoid action induces autophagymediated cell death through stimulation of ER stress in human glioma cells. The Journal of clinical investigation 119(5): 1359-1372.

(70.) Caffarel, M.M., Andradas, C., & Mira, E., et al. (2010) Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Molecular cancer 9: 196.

(71.) Qamri, Z., Preet, A., & Nasser, M.W., et al. (2009) Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer. Molecular cancer therapeutics 8(11): 3117-3129.

(72.) Pharmacoeconomic NCf. (2014) Cost-effectiveness of Delta-9-tetrahydrocannabinol/cannabidiol (Sativex[R]) as add-on treatment, for symptom improvement in patients with moderate to severe spasticity due to MS who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy. http://www.ncpe.ie/wp-content/ uploads/2013/01/Sum mary-v1.pdf.

(73.) Lu, L., Pearce, H., Roome, C., Shearer, J., Lang, I.A., & Stein, K. (2012) Cost effectiveness of oromucosal cannabis-based medicine (Sativex(R)) for spasticity in multiple sclerosis. PharmacoEconomics 30(12): 1157-1171.

(74.) Wilsey, B., Marcotte, T., Deutsch, R., Gouaux, B., Sakai, S., & Donaghe, H. (2013) Low-dose vaporized cannabis significantly improves neuropathic pain. The journal of pain : official journal of the American Pain Society 14(2): 136-148.

(75.) Grant, I., Atkinson, J.H., Gouaux, B., & Wilsey, B. (2012) Medical marijuana: clearing away the smoke. The open neurology journal 6: 18-25.

(76.) Doblin, R.E., & Kleiman, M.A. (1991) Marijuana as antiemetic medicine: a survey of oncologists' experiences and attitudes. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 9(7): 1314-1319.

(77.) Charuvastra, A., Friedmann, P.D., & Stein, M.D. (2005) Physician attitudes regarding the prescription of medical marijuana. Journal of addictive diseases 24(3): 87-93.
Table 1: Pharmacologically active phytocannabinoids

Name                               Abbre-     Structure
                                   viation

[DELTA]-9 tetrahydrocannabinol     THC        [FORMULA NOT
                                              REPRODUCIBLE IN ASCII]

[DELTA]-9-tetrahydrocannabivarin   THCV       [FORMULA NOT
                                              REPRODUCIBLE IN ASCII]

Cannabidiol                        CBD        [FORMULA NOT
                                              REPRODUCIBLE IN ASCII]

Cannabigerol                       CBG        [FORMULA NOT
                                              REPRODUCIBLE IN ASCII]

Cannabichromene                    CBC        [FORMULA NOT
                                              REPRODUCIBLE IN ASCII]

Cannabidivarin                     CBDV       [FORMULA NOT
                                              REPRODUCIBLE IN ASCII]

Cannabinol                         CBN        [FORMULA NOT
                                              REPRODUCIBLE IN ASCII]

Name                               Physiologic Effects

[DELTA]-9 tetrahydrocannabinol     Psychoactive, mild analgesic,
                                   anti-emetic, appetite
                                   stimulant neuroprotective,
                                   reduces neuroinflammation and
                                   stimulates neurogenesis

[DELTA]-9-tetrahydrocannabivarin   Non-psychoactive, anti-
                                   convulsant, antiinflammatory,

Cannabidiol                        Non-psychoactive, relieves
                                   convulsion, inflammation,
                                   anxiety and nausea

Cannabigerol                       Non-psychoactive, relieves
                                   intraocular pressure,
                                   antiinflammatory,
                                   neuroprotective, anti-emetic
                                   stimulates neurogenesis

Cannabichromene                    Non-psychoactive, anti
                                   inflammatory and analgesic
                                   effects

Cannabidivarin                     Non-psychoactive,anti-
                                   convulsive, antiinflammatory

Cannabinol                         Weakly psychoactive
                                   (degradation product of THC),
                                   immunosuppressant activity,
                                   anticonvulsive

Name                               Therapeutic Indication(s)

[DELTA]-9 tetrahydrocannabinol     Pain, Nausea, Nutritional
                                   wasting, Cancer

[DELTA]-9-tetrahydrocannabivarin   Epilepsy and other CNS
                                   disorders hepatic ischemia

Cannabidiol                        Schizophrenia, epilepsy,
                                   cancer

Cannabigerol                       Multiple Sclerosis, Glaucoma
                                   and inflammatory bowel disease

Cannabichromene                    Pain, Cancer

Cannabidivarin                     Epilepsy

Cannabinol                         Epilepsy

Table 2: Companies developing Cannabis-based therapeutics

Company                Product                    Properties

AbbVie                 Marinol[R] (dronabinol)    Synthetic [DELTA]-
                                                  9-THC

Valeant                Cesamet[R] (nabilone)      Synthetic [DELTA]-
Pharmaceuticals                                   9-THC
International Inc

GW Pharma              Sativex[R] (naviximols)    Mixture of extracts
                                                  of cannabis plant
                                                  containing two
                                                  cannabinoids in 1:1
                                                  ratio, [DELTA]-9-
                                                  THC and CBD
                                                  (cannabidiol) in 50%
                                                  alcoholic solution;
                                                  oro-mucosal delivery
                                                  (mouth spray)

                       Epidiolex[R]               CBD (cannabidiol)
                                                  liquid extract from
                                                  genetically-defined
                                                  cannabis strain

                       GWP42003                   Not disclosed

                       GWP42004                   Not disclosed

                       GWP42006                   Cannabidivarin
                                                  (CBDV)

Society for Clinical   Cannador[R]                Oral capsule
Research (Germany)                                containing whole
                                                  plant extract with
                                                  standardized THC:CBD
                                                  ratio of 2:1

Kannalife              Not named                  Cannabis extract-
                                                  semi-synthetic CBD
                                                  (cannabidiol)

Aphios                 APH-080                    Liposomal
                                                  formulation of
                                                  [DELTA]-9-THC

                       APH-1305                   CBG (cannabigerol)
                                                  liposomal-oral
                                                  delivery

Cannabis Sciences      CS-S/BCC-1                 CBN (cannabinol)
                                                  enriched extracts

                       CS-TATI-1                  Plant extract

                       TBN                        CBN (cannabinol)
                                                  plus other
                                                  cannabinoids

Medical Marijuana      TBN                        CBD (cannabidiol)
Sciences                                          extracts plus
                                                  microencapsulation
                                                  technology

Company                Indication(s)          Stage of Development

AbbVie                 Chemotherapy/          FDA/approved for
                       induced nausea/        nausea and vomiting
                       vomiting (CINV); MS    associated CINV
                       neuropathic pain;      (1985) when other
                       HIV/AIDS appetite      anti/emetics fail
                       stimulate              and appetite
                                              stimulant for HIV/
                                              AIDS patients(1992)
                                              Approved in Denmark
                                              for multiple
                                              sclerosis
                                              neuropathic pain
                                              (2003)

Valeant                Management of          Approved in Canada
Pharmaceuticals        nausea/vomiting        (1982); now
International Inc                             available in US and
                                              UK

GW Pharma              Neurologic and         Approved in 27
                       cancer-related pain;   countries outside
                       Spasticity in          US; US Phase III
                       patients with MS       trials for cancer
                                              pain/MS muscle
                                              spasticity; granted
                                              FDA Fast Track
                                              designation

                       Orphan pediatric       Early clinical
                       epilepsy; Dravet       development; granted
                       Syndrome and Lennox-   FDA orphan drug
                       Gastaut syndrome       status

                       Ulcerative colitis     Phase 2a

                       Type 2 diabetes        Phase 2b

                       Adult epilepsy         Phase 1

Society for Clinical   Muscle stiffness; MS   Phase 1/2
Research (Germany)     spasticity-pain;
                       cachexia in cancer
                       patients, post-
                       operative pain
                       management

Kannalife              Hepatic                Preclinical; Seeking
                       Encephalopathy         orphan drug
                                              designation for
                                              clinical development

Aphios                 CINV; Appetite         Preclinical
                       stimulant for HIV
                       and cancer patients

                       MS & other             Preclinical
                       neuroinflammatory
                       neurodegenerative
                       disorders

Company                Indication(s)          Stage of Development

Cannabis Sciences      Oncology               Preclinical

                       Kaposi Sarcoma         Preclinical

                       Anxiety, sleep         R&D
                       disorders,
                       Alzheimers disease

Medical Marijuana      Brain and pancreatic   R&D
Sciences               cancer

Table 3 Current clinical trials for Cannabis-derived pharmaceuticals

Product        Sponsor                      Therapeutic Indication

Cannabis       University of California,    Neuropathic pain, multiple
               Davis Center for Medicinal   sclerosis, spinal cord
               Cannabis Research, VA        injury
               Northern California
               Healthcare System

Cannabis       University of California,    Spinal cord injury pain
               Davis VA Northern
               California Healthcare
               System University of
               California Davis, National
               Institute of Drug Abuse

Cannabis       Center for Medicinal         Diabetic neuropathy
               Cannabis Research

Cannabis       Center for Medicinal         Neuropathic pain
               Cannabis Research

Cannabis       Center for Medicinal         HIV-associated distal,
               Cannabis Research            sensory-predominant
                                            polyneurophathy (DSPN)

Cannabis       Center for Medicinal         Pain, hyperalgesia
               Cannabis Research

Cannabis vs.   University of California,    Multiple Sclerosis
dronabinol,    Davis, National Multiple     spasticity
Marinol        Sclerosis Society
or THC

Cannabis       Center for Medicinal         Multiple Sclerosis
               Cannabis Research            spasticity

Sativex[R]     GW Pharma                    Cancer pain

Sativex[R]     GW Pharma                    Cancer pain

Sativex[R]     GW Pharma; Otsuka            Advanced persistent cancer
               Pharmaceuticals              pain

Sativex[R]     Capital District Health      Neuropathic pain
               Authority Canada             associated with
                                            chemotherapy

Sativex[R]     GW Pharma                    Peripheral neuropathy

Sativex[R]     GW Pharma                    Neuropathic pain

Sativex[R]     GW Pharma                    Neuropathic pain
                                            management

Sativex[R]     GW Pharma                    Diabetic neuropathic pain

Sativex[R]     GW Pharma                    Spinal cord injury pain

Sativex[R]     GW Pharma                    Brachial plexus injury
vs.THC                                      pain

Sativex[R]     GW Pharma                    Central neuropathic pain
                                            due to Multiple Sclerosis

Sativex[R]     GW Pharma                    Central neuropathic pain
                                            due to Multiple Sclerosis

Sativex[R]     GW Pharma                    Multiple Sclerosis, pain,
                                            spasticity

Sativex[R]     GW Pharma                    Pain; Multiple Sclerosis
vs. THC

Sativex[R]     GW Pharma                    Multiple Sclerosis

Sativex[R]     GW Pharma                    Multiple Sclerosis

Sativex[R]     GW Pharma                    Multiple Sclerosis

Sativex[R]     GW Pharma                    Multiple Sclerosis
                                            spasticity

Sativex[R]     GW Pharma                    Multiple Sclerosis
                                            spasticity

Sativex[R]     GW Pharma                    Multiple Sclerosis
                                            spasticity

Sativex[R]     GW Pharma                    Multiple Sclerosis
                                            spasticity

Sativex[R]     GW Pharma                    Multiple Sclerosis
                                            spasticity

Sativex[R]     GW Pharma                    Multiple Sclerosis
                                            Detrusor over activity

Sativex[R]     GW Pharma                    Fluntington's Disease

Sativex[R]     GW Pharma                    Cancer
plus
Temozolomide

Epidiolex      GW Pharma                    Epilepsy, Dravet or
(GWP42003-                                  Lennox-Gastaut Syndromes
P)

Epidiolex      GW Pharma                    Epilepsy, Dravet Syndrome
(GWP42003-
P)

Epidiolex      GW Pharma                    Epilepsy, Lennox-Gastaut
(GWP42003-                                  Seizures
P)

Epidiolex      GW Pharma                    Epilepsy, Lennox-Gastaut
(GWP42003-                                  Seizures
P)

Cannabidiol    GW Pharma Fancea 66          Sturge-Weber Syndrome
(CBD)          Foundation

GWP42003       GW Pharma                    Schizophrenia or related
                                            psychotic disorder

Cannabidiol    Meir Medical Center          Ulcerative Colitis
(CBD)

Cannabinol     Meir Medical Center          Crohn's Disease
(CBD) and
THC

Cannabidiol    Hadassah Medical             Solid Tumors
(CBD)          Organization

Cannabidiol    Rabin Medical Center         Graft vs. Host Disease
(CBD)

Product        Study Title

Cannabis       Effects of Vaporized Marijuana on Neuropathic Pain

Cannabis       Vaporized Cannabis and Spinal Cord Injury Pain

Cannabis       Efficacy of Inhaled Cannabis in Diabetic Painful
               Peripheral Neuropathy

Cannabis       Effects of Smoked Marijuana on Neuropathic Pain

Cannabis       Medicinal Cannabis for Painful HIV Neuropathy

Cannabis       Analgesic Efficacy of Smoked Cannabis

Cannabis vs.   Cannabis for Spasticity in Multiple Sclerosis
dronabinol,
Marinol
or THC

Cannabis       Short-Term Effects of Medicinal Cannabis Therapy on
               Spasticity in Multiple Sclerosis

Sativex[R]     A Study of Sativex[R] for Pain Relief in Patients With
               Advanced Malignancy (SPRAY)

Sativex[R]     Study to Compare the Safety and Tolerability of
               Sativex[R] in Patients With Cancer Related Pain

Sativex[R]     Sativex[R] for Relieving Persistent Pain in Patients
               With Advanced Cancer (SPRAY III)

Sativex[R]     Sativex for Treatment of Chemotherapy Induced
               Neuropathic Pain

Sativex[R]     A Study of Sativex[R] for Pain Relief of Peripheral
               Neuropathic Pain, Associated With Allodynia

Sativex[R]     A Study to Compare the Safety and Tolerability of
               Sativex[R] in Patients With Neuropathic Pain

Sativex[R]     A Study to Determine the Maintenance of Effect After
               Long-term Treatment of Sativex[R] in Subjects With
               Neuropathic Pain

Sativex[R]     A Study of Sativex[R] for Pain Relief Due to Diabetic
               Neuropathy

Sativex[R]     A Study of Cannabis Based Medicine Extracts and Placebo
               in Patients With Pain Due to Spinal Cord Injury

Sativex[R]     A Study to Compare Sublingual Cannabis Based Medicine
vs. THC        Extracts With Placebo to Treat Brachial Plexus Injury
               Pain

Sativex[R]     A Study of Sativex in the Treatment of Central
               Neuropathic Pain Due to Multiple Sclerosis

Sativex[R]     Sativex Versus Placebo When Added to Existing Treatment
               for Central Neuropathic Pain in MS

Sativex[R]     A Study of the Long-term Safety of Sativex Use

Sativex[R]     A Study to Evaluate the Effects of Cannabis Based
vs.THC         Medicine in Patients With Pain of Neurological Origin

Sativex[R]     Neurophysiological Study of Sativex in Multiple
               Sclerosis (MS) Spasticity (NS-MSS)

Sativex[R]     An Study to Investigate the Efficacy of Delta-9-
               tetrahydrocannabinol (THC) and Cannabidiol (CBD) in
               Multiple Sclerosis

Sativex[R]     An Investigation of Delta-9-tetrahydrocan nabinol (THC)
               and Cannabidiol (CBD) in Multiple Sclerosis Patients

Sativex[R]     A Study of Sativex[R] for Relief of Spasticity in
               Subjects With Multiple Sclerosis

Sativex[R]     A Study of the Safety and Effectiveness of Sativex[R],
               for the Relief of Symptoms of Spasticity in Subjects,
               From Phase B, With Multiple Sclerosis (MS)

Sativex[R]     Evaluate the Maintenance of Effect After Longterm
               Treatment With Sativex[R] in Subjects With Symptoms of
               Spasticity Due to Multiple Sclerosis

Sativex[R]     A Study to Evaluate the Efficacy of Sativex in
               Relieving Symptoms of Spasticity Due to Multiple
               Sclerosis

Sativex[R]     A Randomized Study of Sativex on Cognitive Function and
               Mood: Multiple Sclerosis Patients

Sativex[R]     A Parallel Group Study to Compare Sativex[R] With
               Placebo in the Treatment of Detrusor Overactivity in
               Patients With Multiple Sclerosis

Sativex[R]     Neuroprotection by Cannabinoids in Huntington's
               Disease

Sativex[R]     A Safety Study of Sativex in Combination With Dose-
plus           intense Temozolomide in Patients With Recurrent
Temozolomide   Glioblastoma

Epidiolex      An Open Label Extension Study of Cannabidiol (GWP42003-
(GWP42003-     P) in Children and Young Adults With Dravet or Lennox-
P)             Gastaut Syndromes

Epidiolex      A Study to Investigate the Efficacy and Safety of
(GWP42003-     Cannabidiol (GWP42003-P) in Children and Young Adults
P)             With Dravet Syndrome

Epidiolex      A Study to Investigate the Efficacy and Safety of
(GWP42003-     Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment
P)             for Seizures Associated With Lennox-Gastaut Syndrome in
               Children and Adults

Epidiolex      A Study to Investigate the Efficacy and Safety of
(GWP42003-     Cannabidiol (GWP42003-P; CBD) as Adjunctive Treatment
P)             for Seizures Associated With Lennox-Gastaut Syndrome in
               Children and Adults

Cannabidiol    Cannabidiol Expanded Access Study in Medically
(CBD)          Refractory Sturge-Weber Syndrome

GWP42003       A Study of GWP42003 as Adjunctive Therapy in the First
               Line Treatment of Schizophrenia or Related Psychotic
               Disorder

Cannabidiol    Cannabidiol for Inflammatory Bowel Disease
(CBD)

Cannabinol     Combined THC and CBD Drops for Treatment of Crohn's
(CBD) and      Disease
THC

Cannabidiol    A Study: Pure CBD as Single-agent for Solid Tumor
(CBD)

Cannabidiol    Safety and Efficacy of Cannabidiol for Grade I/II Acute
(CBD)          Graft Versus Host Disease (GVHD) After Allogeneic Stem
               Cell Transplantation

Product        Phase    ClinTrial.gov
                        Identifier

Cannabis         2      NCT01037088

Cannabis         2      NCT01555983

Cannabis         2      NCT00781001

Cannabis         2      NCT00254761

Cannabis         2      NCT00255580

Cannabis         2      NCT00241579

Cannabis vs.     2      NCT00682929
dronabinol,
Marinol
orTHC

Cannabis         2      NCT00248378

Sativex[R]       3      NCT00674609

Sativex[R]       3      NCT00675948

Sativex[R]       3      NCT01361607

Sativex[R]       3      NCT00872144

Sativex[R]       3      NCT00710554

Sativex[R]       3      NCT00713323

Sativex[R]       3      NCT00713817

Sativex[R]       3      NCT00710424

Sativex[R]       3      NCT01606202

Sativex[R]       3      NCT01606189
vs.THC

Sativex[R]       3      NCT01604265

Sativex[R]       3      NCT00391079

Sativex[R]       3      NCT01606137

Sativex[R]       3      NCT01606176
vs.THC

Sativex[R]       3      NCT01538225

Sativex[R]       3      NCT01610713

Sativex[R]       3      NCT01610700

Sativex[R]       3      NCT00711646

Sativex[R]       3      NCT00681538

Sativex[R]       3      NCT00702468

Sativex[R]       3      NCT01599234

Sativex[R]       4      NCT01964547

Sativex[R]       3      NCT00678795

Sativex[R]       2      NCT01502046

Sativex[R]       2      NCT01812603
plus
Temozolomide

Epidiolex        3      NCT02224573
(GWP42003-
P)

Epidiolex        3      NCT02224703
(GWP42003-
P)

Epidiolex        3      NCT02224560
(GWP42003-
P)

Epidiolex        3      NCT02224690
(GWP42003-
P)

Cannabidiol      2      NCT02332655
(CBD)

GWP42003         2      NCT02006628

Cannabidiol      2      NCT01037322
(CBD)

Cannabinol       2      NCT01826188
(CBD) and
THC

Cannabidiol      2      NCT02255292
(CBD)

Cannabidiol      2      NCT01596075
(CBD)
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Author:Mintz, Clifford S.; Nison, Evan; Fabrizio, A.J.
Publication:Journal of Commercial Biotechnology
Geographic Code:9CHIN
Date:Jul 1, 2015
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