Thursday, 3 July 2014

FDA grants orphan drug designation to Insys Therapeutics’ pharmaceutical cannabidiol


Systematic (IUPAC) name
Clinical data
Trade namesEpidiolex
AHFS/Drugs.comInternational Drug Names
Legal statusSchedule I (US)Schedule II (Can)(THC - Schedule/Level I; THC and CBD two main chemicals in cannabis)
Pharmacokinetic data
Bioavailability13-19% (oral),[1] 11-45% (mean 31%; inhaled)[2]
Half-life9 h[1]
CAS number13956-29-1 Yes
ATC codeNone
PubChemCID 644019
ChemSpider24593618 Yes
Chemical data
Mol. mass314.4636
Physical data
Melt. point66 °C (151 °F)
Boiling point180 °C (356 °F)
(range: 160–180 °C)[3]

FDA grants orphan drug designation to Insys Therapeutics’ pharmaceutical cannabidiol - Pharmaceutical Technology
US-based specialty pharmaceutical company Insys Therapeutics has obtained orphan drug designation from the US Food and Drug Administration (FDA) for its pharmaceutical cannabidiol for treatment of Lennox-Gastaut Syndrome.

Insys Therapeutics president and CEO Michael Babich said: "With no cure and persistence of seizures with current antiepileptic medications, the orphan drug designation recognises the significant, unmet need that exists among children with this severe form of epilepsy and the teams who provide their care.
"We have the unique opportunity to test a controlled pharmaceutical CBD product for Lennox-Gastaut Syndrome, and our company is committed to advancing cannabinoid therapies that have the potential to provide significant medical benefits to patients across multiple indications.
"With no cure and persistence of seizures with current antiepileptic medications, the orphan drug designation recognises the significant, unmet need that exists among children with this severe form of epilepsy and the teams who provide their care."
"We expect to file an investigational new drug application (IND) for CBD in the second half of 2014."

Cannabidiol (CBD) is one of at least 60 active cannabinoids identified in cannabis.[4] It is a major phytocannabinoid, accounting for up to 40% of the plant's extract.[5] CBD is considered to have a wider scope of medical applications than tetrahydrocannabinol(THC).[5] An orally-administered liquid containing CBD has received orphan drug status in the US, for use as a treatment for dravet syndrome under the brand name, Epidiolex.[6]

Clinical applications

The bud of a Cannabis sativa flower coated with trichomes

Antimicrobial actions

CBD absorbed transcutaneously may attenuate the increased sebum production at the root of acne, according to an untested hypothesis.[7]

Neurological effects

A 2010 study found that strains of cannabis containing higher concentrations of cannabidiol did not produce short-term memory impairment vs. strains with similar concentrations of THC, but lower concentrations of CBD. The researchers attributed this attenuation of memory effects to CBD's role as a CB1 antagonist. Transdermal CBD is neuroprotective in animals.[8]
Cannabidiol's strong antioxidant properties have been shown to play a role in the compound's neuroprotective and anti-ischemiceffects.[9]
Parkinson's disease
It has been proposed that CBD may help people with Parkinson's disease, but promising results in animal experiments were not confirmed when CBD was trialled in humans.[10]

Psychotropic effect

CBD has anti-psychotic effects and may counteract the potential psychotomimetic effects of THC on individuals with latentschizophrenia;[5] some reports show it to be an alternative treatment for schizophrenia that is safe and well-tolerated.[11] Studies have shown CBD may reduce schizophrenic symptoms due to its apparent ability to stabilize disrupted or disabled NMDA receptor pathways in the brain, which are shared and sometimes contested by norepinephrine and GABA.[11][12] Leweke et al. performed a double blind, 4 week, explorative controlled clinical trial to compare the effects of purified cannabidiol and the atypical antipsychoticamisulpride on improving the symptoms of schizophrenia in 42 patients with acute paranoid schizophrenia.
Both treatments were associated with a significant decrease of psychotic symptoms after 2 and 4 weeks as assessed by Brief Psychiatric Rating Scale andPositive and Negative Syndrome Scale. While there was no statistical difference between the two treatment groups, cannabidiol induced significantly fewer side effects (extrapyramidal symptoms, increase in prolactin, weight gain) when compared to amisulpride.[13]
Studies have shown cannabidiol decreases activity of the limbic system[14] and decreases social isolation induced by THC.[15] Cannabidiol has also been shown to reduce anxiety in social anxiety disorder.[16][17] However, chronic cannabidiol administration in rats was recently found to produce anxiogenic-like effects, indicating that prolonged treatment with cannabidiol might incite anxiogenic effects.[18]
Cannabidiol has demonstrated antidepressant-like effects in animal models of depression.[19][20][21]


The American Cancer Society says: "There is no available scientific evidence from controlled studies in humans that cannabinoids can cure or treat cancer."[22] Laboratory experiments have been performed on the potential use of cannabinoids for cancer therapy but as of 2013 results have been contradictory and knowledge remains poor.[23] Cannabinoids have been recommended for cancer pain but the adverse effects may make them a less than ideal treatment; two cannabinoid-based medicines have been approved as a backup remedy for nausea associated withchemotherapy.[4]

Dravet syndrome

Dravet syndrome is a rare form of epilepsy that is difficult to treat. Dravet syndrome, also known as Severe Myoclonic Epilepsy of Infancy (SMEI), is a rare and catastrophic form of intractable epilepsy that begins in infancy. Initial seizures are most often prolonged events and in the second year of life other seizure types begin to emerge.[24] While high profile and anecdotal reports have sparked interest in treatment with cannabinoids,[25] there is insufficient medical evidence to draw conclusions about their safety or efficacy.[25][26]

CBD-enhanced cannabis

Decades ago, selective breeding by growers in US dramatically lowered the CBD content of cannabis; their customers preferred varietals that were more mind-altering due to a higher THC, lower CBD content.[27] To meet the demands of medical cannabis patients, growers are currently developing more CBD-rich strains.[28]
In November 2012, Tikun Olam, an Israeli medical cannabis facility announced a new strain of the plant which has only cannabidiol as an active ingredient, and virtually no THC, providing some of the medicinal benefits of cannabis without the euphoria.[29][30] The researchers said the cannabis plant, enriched with CBD, "can be used for treating diseases like rheumatoid arthritis, colitis, liver inflammation, heart disease and diabetes". Research on CBD enhanced cannabis began in 2009, resulting in Avidekel, a cannabis strain that contains 15.8% CBD and less than 1% THC. Raphael Mechoulam, a cannabinoid researcher, said "...Avidekel is thought to be the first CBD-enriched cannabis plant with no THC to have been developed in Israel".[31]



Cannabidiol has a very low affinity for CB1 and CB2 receptors but acts as an indirect antagonist of their agonists.[9] While one would assume that this would cause cannabidiol to reduce the effects of THC, it may potentiate THC's effects by increasing CB1 receptor density or through another CB1-related mechanism.[32] It is also an inverse agonist of CB2receptors.[9][33] Recently, it was found to be an antagonist at the putative new cannabinoid receptor, GPR55, a GPCR expressed in the caudate nucleus and putamen.[34]Cannabidiol has also been shown to act as a 5-HT1A receptor agonist,[35] an action which is involved in its antidepressant,[19][36] anxiolytic,[36][37] and neuroprotective[38][39]effects. Cannabidiol is an allosteric modulator of μ and δ-opioid receptors.[40] Cannabidiol's pharmacologial effects have also been attributed to PPAR-γ receptor agonism andintracellular calcium release.[5]

Pharmacokinetic interactions

There is some preclinical evidence to suggest that cannabidiol may reduce THC clearance, modestly increasing THC's plasma concentrations resulting in a greater amount of THC available to receptors, increasing the effect of THC in a dose-dependent manner.[41][42] Despite this the available evidence in humans suggests no significant effect of CBD on THC plasma levels.[43]

Pharmaceutical preparations

Nabiximols (USAN, trade name Sativex) is an aerosolized mist for oral administration containing a near 1:1 ratio of CBD and THC. The drug was approved by Canadian authorities in 2005 to alleviate pain associated with multiple sclerosis.[44][45][46]


Cannabidiol numbering
7 double bond isomers and their 30 stereoisomers
Formal numberingTerpenoid numberingNumber of stereoisomersNatural occurrenceConvention on Psychotropic SubstancesScheduleStructure
Short nameChiral centersFull nameShort nameChiral centers
Δ5-cannabidiol1 and 32-(6-isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ4-cannabidiol1 and 34Nounscheduled2-(6-Isopropenyl-3-methyl-5-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png
Δ4-cannabidiol1, 3 and 62-(6-isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ5-cannabidiol1, 3 and 48Nounscheduled2-(6-Isopropenyl-3-methyl-4-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png
Δ3-cannabidiol1 and 62-(6-isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ6-cannabidiol3 and 44 ?unscheduled2-(6-Isopropenyl-3-methyl-3-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png
Δ3,7-cannabidiol1 and 62-(6-isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediolΔ1,7-cannabidiol3 and 44Nounscheduled2-(6-Isopropenyl-3-methylenecyclohex-1-yl)-5-pentyl-1,3-benzenediol.png
Δ2-cannabidiol1 and 62-(6-isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ1-cannabidiol3 and 44Yesunscheduled2-(6-Isopropenyl-3-methyl-2-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png
Δ1-cannabidiol3 and 62-(6-isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediolΔ2-cannabidiol1 and 44Nounscheduled2-(6-Isopropenyl-3-methyl-1-cyclohexen-1-yl)-5-pentyl-1,3-benzenediol.png


Cannabidiol is insoluble in water but soluble in organic solvents, such as pentane. At room temperature it is a colorless crystalline solid.[47] In strongly basic medium and the presence of air it is oxidized to a quinone.[48] Under acidic conditions it cyclizes to THC.[49] The synthesis of cannabidiol has been accomplished by several research groups.[50][51][52]!divAbstract!divAbstract


Cannabis produces CBD-carboxylic acid through the same metabolic pathway as THC, until the last step, where CBDA synthase performs catalysis instead of THCA synthase.[53]

Legal status

Cannabidiol is not scheduled by the Convention on Psychotropic Substances.
Cannabidiol is a Schedule II drug in Canada.[54]
Cannabidiol's legal status in the United States:
The DEA Drug Schedule classifies synthetic THC (Tetrahydrocannabinol) as a schedule III substance (eg Marinol); while the natural marijuana plant is listed as Schedule I. Cannabidiol is not named specifically on the list.[55] However the CSA does mention all natural Phytocannabinoids in Schedule 1 Code 7372, which would include CBD.[55]
Marijuana (along with all of its cannabinoids) is defined by 21 U.S.C. §802(16), which is part of the Controlled Substances Act.[56][57][58] There is an exemption for certain Hemp products produced abroad. Under this exception, what are known as industrial hemp-finished products are legally imported into the United States each year. Hemp finished products which meet the specific definitions including hemp oil which may contain cannabidiol are legal in the United States but aren't used for getting high.[59]
Some cannabidiol oil is derived from marijuana and therefore contains higher levels of THC.[60] This type of cannabidiol oil would be considered a Schedule I as a result of the THC present.[60]

US patent

In October 2003, U.S. patent #6630507 entitled "Cannabinoids as antioxidants and neuroprotectants" was assigned to "The United States Of America As Represented By The Department Of Health And Human Services." The patent was filed in April 1999 and listed as the inventors: Aidan J. Hampson, Julius Axelrod, and Maurizio Grimaldi, who all held positions at the National Institute of Mental Health (NIMH) in Bethesda, MD, which is part of the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). The patent mentions cannabidiol's ability as an antiepileptic, to lower intraocular pressure in the treatment of glaucoma, lack of toxicity or serious side effects in large acute doses, its neuroprotectant properties, its ability to prevent neurotoxicity mediated by NMDA, AMPA, or kainate receptors; its ability to attenuate glutamate toxicity, its ability to protect against cellular damage, its ability to protect brains from ischemic damage, its anxiolytic effect, and its superior antioxidant activity which can be used in the prophylaxis and treatment of oxidation associated diseases.[61]
"Oxidative associated diseases include, without limitation, free radical associated diseases, such as ischemia, ischemic reperfusion injury, inflammatory diseases, systemic lupus erythematosus, myocardial ischemia or infarction, cerebrovascular accidents (such as a thromboembolic or hemorrhagic stroke) that can lead to ischemia or an infarct in the brain, operative ischemia, traumatic hemorrhage (for example a hypovolemic stroke that can lead to CNS hypoxia or anoxia), spinal cord trauma, Down's syndrome, Crohn's disease, autoimmune diseases (e.g. rheumatoid arthritis or diabetes), cataract formation, uveitis, emphysema, gastric ulcers, oxygen toxicity, neoplasia, undesired cellular apoptosis, radiation sickness, and others. The present invention is believed to be particularly beneficial in the treatment of oxidative associated diseases of the CNS, because of the ability of the cannabinoids to cross the blood brain barrier and exert their antioxidant effects in the brain. In particular embodiments, the pharmaceutical composition of the present invention is used for preventing, arresting, or treating neurological damage in Parkinson's disease, Alzheimer's disease and HIV dementia; autoimmune neurodegeneration of the type that can occur in encephalitis, and hypoxic or anoxic neuronal damage that can result from apnea, respiratory arrest or cardiac arrest, and anoxia caused by drowning, brain surgery or trauma (such as concussion or spinal cord shock)."[61]
On November 17, 2011, the Federal Register published that the National Institutes of Health of the United States Department of Health and Human Services was "contemplating the grant of an exclusive patent license to practice the invention embodied in U.S. Patent 6,630,507" to the company KannaLife based in New York, for the development and sale of cannabinoid and cannabidiol based therapeutics for the treatment of hepatic encephalopathy in humans.[62][63][64]


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External links

  • Project CBD Non-profit educational service dedicated to promoting and publicizing research into the medical utility of cannabidiol.



Seven Expanded Access INDs granted by FDA to U.S. 
physicians to treat with Epidiolex 125 children suffering 
from intractable epilepsy syndromes -
LONDON, Nov. 15, 2013
GW Pharmaceuticals plc (AIM: GWP, Nasdaq: GWPH, “GW”) announced today that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation for Epidiolex(R), our product candidate that contains plant-derived Cannabidiol (CBD) as its active ingredient, for use in treating children with Dravet syndrome, a rare and severe form of infantile-onset, genetic, drug-resistant epilepsy syndrome. Epidiolex is an oral liquid formulation of a highly purified extract of CBD, a non-psychoactive molecule from the cannabis plant. Following receipt of this orphan designation, GW anticipates holding a pre-IND meeting with the FDA in the near future to discuss a development plan for Epidiolex in Dravet syndrome.
Dravet syndrome is a rare pediatric epilepsy syndrome with a distinctive but complex electroclinical presentation. Onset of Dravet syndrome occurs during the first year of life with clonic and tonic-clonic seizures in previously healthy and developmentally normal infants. Prognosis is poor and patients typically develop intellectual disability and life-long ongoing seizures. There are approximately 5,440 patients with Dravet in the United States and an estimated 6,710 Dravet patients in Europe. These figures may be an underestimate as this syndrome is reportedly underdiagnosed.
In addition to GW’s clinical development program for Epidiolex in Dravet syndrome, which is expected to commence in 2014, GW has also made arrangements to enable independent U.S. pediatric epilepsy specialists to treat high need pediatric epilepsy cases with Epidiolex immediately. To date in 2013, a total of seven “expanded access” INDs have been granted by the FDA to U.S. clinicians to allow treatment with Epidiolex of approximately 125 children with epilepsy. These children suffer from Dravet syndrome, Lennox-Gastaut syndrome, and other pediatric epilepsy syndromes. GW is aware of further interest from additional U.S. and ex-U.S. physicians to host similar INDs for Epidiolex. GW expects data generated under these INDs to provide useful observational data during 2014 on the effect of Epidiolex in the treatment of a range of pediatric epilepsy syndromes.
“I, together with many colleagues in the U.S. who specialize in the treatment of childhood epilepsy, very much welcome the opportunity to investigate Epidiolex in the treatment of Dravet syndrome. The FDA’s timely approval of the orphan drug designation for Epidiolex in Dravet syndrome is a key milestone that comes after many years of reported clinical cases that suggest encouraging evidence of efficacy for CBD in this intractable condition,” stated Dr. Orrin Devinsky, Professor of Neurology, Neurosurgery and Psychiatry in New York City. “With GW now making plans to advance Epidiolex through an FDA development program, we have the prospect for the first time of fully understanding the science of CBD in epilepsy with a view to making an appropriately tested and approved prescription medicine available in the future for children who suffer from this debilitating disease.”
“GW is proud to be at the forefront of this important new program to treat children with Dravet Syndrome and potentially other forms of intractable childhood epilepsy. For families in these circumstances, their lives are significantly impacted by constant and often times very severe seizures in children where all options to control these seizures have been exhausted,” stated Dr. Stephen Wright, GW’s R&D Director. “GW intends to advance a full clinical development program for Epidiolex in Dravet syndrome as quickly as possible, whilst at the same time helping families in the short term through supporting physician-led INDs to treat intractable cases. Through its efforts, GW aims to provide the necessary evidence to confirm the promise of CBD in epilepsy and ultimately enabling children to have access to an FDA-approved prescription CBD medicine.”
“This orphan program for Epidiolex in childhood epilepsy is an important corporate strategic priority for GW. Following receipt of today’s orphan designation, GW now intends to commence discussions with the FDA regarding the U.S. regulatory pathway for Epidiolex,” stated Justin Gover, GW’s Chief Executive Officer. “GW intends to pursue this development in-house and retains full commercial rights to Epidiolex.”
About Orphan Drug Designation
Under the Orphan Drug Act, the FDA may grant orphan drug designation to drugs intended to treat a rare disease or condition — generally a disease or condition that affects fewer than 200,000 individuals in the U.S. The first NDA applicant to receive FDA approval for a particular active ingredient to treat a particular disease with FDA orphan drug designation is entitled to a seven-year exclusive marketing period in the U.S. for that product, for that indication.
About GW Pharmaceuticals plc
Founded in 1998, GW is a biopharmaceutical company focused on discovering, developing and commercializing novel therapeutics from its proprietary cannabinoid product platform in a broad range of disease areas. GW commercialized the world’s first plant-derived cannabinoid prescription drug, Sativex(R), which is approved for the treatment of spasticity due to multiple sclerosis in 22 countries. Sativex is also in Phase 3 clinical development as a potential treatment of pain in people with advanced cancer. This Phase 3 program is intended to support the submission of a New Drug Application for Sativex in cancer pain with the U.S. Food and Drug Administration and in other markets around the world. GW has established a world leading position in the development of plant-derived cannabinoid therapeutics and has a deep pipeline of additional clinical-stage cannabinoid product candidates targeting epilepsy (including an orphan pediatric epilepsy program), Type 2 diabetes, ulcerative colitis, glioma and schizophrenia. For further information, please visit
Cannabidiol (CBD) is one of at least 85 cannabinoids found in cannabis.It is a major constituent of the plant, second totetrahydrocannabinol (THC), and represents up to 40% in its extracts. Compared with THC, cannabidiol is not psychoactive in healthy individuals, and is considered to have a wider scope of medical applications than THC, including to epilepsy, multiple sclerosis spasms, anxiety disorders, bipolar disorder,schizophrenia,nausea, convulsion and inflammation, as well as inhibiting cancer cell growth. There is some preclinical evidence from studies in animals that suggests CBD may modestly reduce the clearance of THC from the body by interfering with its metabolism.Cannabidiol has displayed sedative effects in animal tests. Other research indicates that CBD increases alertness. CBD has been shown to reduce growth of aggressive human breast cancer cells in vitro, and to reduce their invasiveness.

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