Cannabidiol as a potential treatment for anxiety disorders Esther Blessing, MD PhD
Overview History and of cannabidiol (CBD) and cannabis Safety and tolerability of CBD CBD pharmacology Clinical need for anxiolytic drugs Evidence for CBD as an anxiolytic Current clinical research with CBD and cannabinoid related drugs
What is cannabidiol? CBD is one of ~ 100 cannabinoid compounds unique to Cannabis plants CBD does not produce psychoactive effects like 9- THC, the other main cannabinoid Cannabinoids produced by trichome glands in hairs of buds on female Cannabis plants Female plants Flower buds Trichome glands Dried bud
Cannabis Commonly used psychoactive substance worldwide Multiple varieties varying in cannabinoid composition C. Indica C. Sativa Used for fiber Sedative CBD:THC ratio Strong high THC:CBD ratio Increasing legalization and medical use
History of medicinal cannabis use (1) ~ 8,000 BCE use in China as rope, later used for garments, paper, and medicine 2700 BCE Used in ancient Egypt, India, Africa, Greece, Rome and Arab world to treat multiple ailments 1937 - Marijuana Tax Act- prohibited use, AMA opposed 1964 - delta-9-tetrahydrocannabinol (THC) isolated by Raphael Mechoulam 1972 - THC determined to be drug with no accepted use 1976 - Randell gets IND to treat glaucoma in court battle
History of medicinal cannabis use (2) 1970-90s Small randomized clinical trials for treating epilepsy 1970-90s Human and animal experimental trials show low-dose THC is anxiolytic, high dose is anxiogenic and pro-psychotic 1985-1995 Synthetic THC (eg marinol and cesamet) approved by FDA for treatment of cancer associated nausea, pain, loss of appetite 1996 CB1 receptor cloned, endocannabinoid system discovered
History of medicinal cannabis use (2) 1996 - California legalizes Cannabis for AIDS, cancer treatment 2000s Role of the endocannabinoid system in emotional brain discovered, explosion in cannabinoid research 2010s Sativex: 50/50 THC/CBD oral spray approved for spasticity in MS in the UK 2015 Completion of Phase II trials for Epidiolex: pure CBD oral for treatment of childhood epilepsy in the US
Cannabidiol Plant-derived Cannabinoids ~ 100 different types in Cannabis Cannabinol Cannabigerol Tetrahydrocannabivarin Cannabichromene Izzo et al, Cell, 2009 Fo Δ 9 Tetrahydro cannabinol
Endocannabinoids (ecbs) (Endogenous activators of the cannabinoid receptor) ecbs: Anandamide & 2-AG Enzymes FAAH and MGL CB1 and CB2 receptors receptor Other receptors, eg TRP receptors DiMarzo 2004
The Cannabinoid receptors (Endogenous activators of the cannabinoid receptor)
Endocannabinoids (ecbs) (Endogenous activators of the cannabinoid receptor) ecbs synthesized from cell lipids in response to strong neuronal activity ecbs activate the CB1 receptor and other receptors on presynaptic GABA and glutamate neurons, leads to neurotransmitter inhibition Brain-wide and in periphery Roles in appetite, inflammation, emotion, nociception, etc
Endocannabinoids currently an anxiolytic drug target
Increasing interest in cannabidiol CBD characterized in 1963 by Raphael Mechoulam
Multiple clinical uses for CBD Anxiolytic / sedative 1970-80s initial acute dosing studies in rat and human show anxiolytic effects, reversing effects of THC (Zuardi et al) Anti-epileptic 1970-1990 controlled clinical trials with CBD in epilepsy, 2015 Orin Devinsky, NYU Langone, JAMA neurology, Epidiolex (pure CBD) reduces seizures in Dravet-syndrome Anti-inflammatory, anti-emetic, antineoplastic, neuroprotective, anti-diabetic Devinsky et al, Epilepsia, 2014 Campos et al, Phil Trans Lon, 2012
Overview Safety and tolerability of CBD CBD pharmacology Clinical need for anxiolytic drugs Evidence for CBD as an anxiolytic Current clinical research with CBD and cannabinoid related drugs
Safety and tolerability of CBD Well tolerated across a wide dose range, up to 1500 mg/day oral no reported psychomotor slowing, negative mood effects, or vital sign abnormalities, although some mild sedative effects (Bergamaschi, 2011). Pediatric phase III trials completed, (Devinsky et al, 2015) Drug-drug interactions: potent inhibitor of P450 isozymes, primarily CYP2C and CYP3A classes may potentiate THC effects when given in combination
CBD pharmacology (1) *Indirect effects Campos et al, 2012; McPartland et al, 2015; Ibeas et al, 2015
CBD pharmacology (2) Complicated! ~ 65 targets, mostly enzymes Not clear whether in vitro receptor data represents physiological in vivo effects Disputed whether CBD acts on the endocannabinioid system Many targets remain uncharacterized McPartland et al, 2015; Ibeas et al, 2015
Overview Clinical need for anxiolytic drugs Evidence for CBD as an anxiolytic Current clinical research with CBD and cannabinoid related drugs
Anxiety disorders overview Combined US lifetime prevalence of 29 %, highest of any mental disorder, immense social and economic burden DSM-4 Trauma DSM5
Current anxiolytic medications Serotonin reuptake inhibitors; serotonin norepinephrine DSM-4 reuptake inhibitors; benzodiazepines; MAO inhibitors; tricyclic antidepressant drugs; partial 5-hydroxytryptamine (5-HT) 1A receptor agonists Anticonvulsants and atypical antipsychotics also used to treat PTSD Associated with limited response rates and residual symptoms, particularly in PTSD Adverse effects limit tolerability and adherence
Barriers to drug development 3-12 billion to the development of new agents, including failure costs Unclear pipelines: preclinical anxiety tests lack not only predictive validity (the ability to predict new drugs) but also postdictive validity (sensitivity to existing drugs). Forbes.com: The truly staggering cost of investing new drugs
Overview Evidence for CBD as an anxiolytic Current clinical research with CBD and cannabinoid related drugs
Converging evidence for CBD as an anxiolytic 1. Epidemiologic 2. Preclinical (animal model) evidence 3. Role for endocannabinoids in anxiety 4. Human experimental data Cannabidiol as a Potential Treatment for Anxiety Disorders Blessing EM, Steenkamp MM, Manzanares J, Marmar CR Neurotherapeutics, 2015
Epidemiological evidence Limited: Reports marijuana with higher CBD:THC ratio reduces risk of psychosis (Manseau et al, 2015; Iseger et al, 2015) Anecdotal evidence that smoking marijuana reduces anxiety, but anxiogenic effects also reported, complex causal interactions possible, requires further controlled studies also not specific for CBD
Preclinical evidence Strong: CBD reduces multiple anxiety behaviors in over 50 studies, including both unconditioned and conditioned behaviors Suggests potential for treating PTSD, GAD and PD However: U-shaped dose curve evident (maybe due to TRP channel activation), also different effective doses in different paradigms. Chronic data lacking.
Human experimental evidence (1) Strong psychological data: Multiple studies: CBD (300-600 mg) reduces anxiety associated with public speaking, imaging procedure anxiety and THC ingestion in normal and SAD subjects (Zuardi) CBD may enhance extinction of conditioned fear (Das 2012) However: No dose finding studies published
Human experimental evidence (2) Moderate neuroimaging evidence Several small sample functional imaging studies suggest oral CBD (300 600 mg) reduces activation in the amygdala and other brain areas associated with anxiety (Fusar-Poli et al)
CBD as an anxiolytic: evidence summary Moderate-strong preclinical and acute human experimental evidence to suggest broad anxiolytic effects Chronic dosing studies in clinical populations needed Unknown what the most effective anxiolytic dose, dose-finding studies needed
Overview Current clinical research issues with CBD and cannabinoid related drugs
Current landscape for CBD and anxiety Chronic dosing with dose-finding studies in clinical populations needed Stigma associated with CBD originating from a schedule I drug persist Limited sources of pure with Phase I safety data available likely to increase with changing legal landscape Stay tuned!!