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)
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.
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.
Clifford S. Mintz, BioInsights, Inc, US. Email1: cliffmz@ yahoo.com
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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|
|Date:||Jul 1, 2015|
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