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CANNABIDIOL (CBD)
THE BE ALL END ALL?
John Schaeffer, DO
PMG neurology specialists
Clinical associate professor
Department of neurology
University of Washington school of medicine
CANNABIS
BRIEF HISTORY
Indiginous to Central and South Asia
Used for millenia to produce hemp for rope, clothing and paper
Used since about 2700 BCE, originally in China, for a large variety of conditions, including:
- gout
- rheumatism
- gastrointestinal disorders
- absent-mindedness
- epilepsy
- fever
CANNABIS
BRIEF HISTORY
Two major neuroactive components
1. Delta-9 Tetrahydro-cannabinol (THC)
a. Psychoactive, produces the high
b. Binds to CB1 and CB2 receptors
2. Cannabidiol (CBD)
a. Non psychoactive (does not produce a high)
b. May attenuate psychoactive effects of THC
c. Binds weakly to CB1 receptors
d. Does not bind to CB2 receptors
e. Multiple other possible mechanisms
CANNABIS
BRIEF HISTORY
Species
1. Sativa
a. High THC:CBD ratio
b. Stimulating
2. Indica
a. Lower THC:CBD
b. Sedating
ENDOCANNABINOID SYSTEM
CB1 receptors
1. Largely located in brain (high)
2. Cloned in 1990
3. Cause neuronal inhibition by decreasing neurotransmitter release
CB2 receptors
1. Largely in immune and hematopoietic systems
2. Cloned 1993
Endocannabinoids (anandamide)
1. Partial agonist at CB1 and CB2 receptors
2. Can diminish psychoactive effects of THC
3. TRPV1 agonist
CBD
MECHANISMS
Inhibits orphan G-protein-coupled receptor (GPR55)
1. Decreases pre-synaptic calcium influx
2. Decreases excitatory neurotransmitter release
Enhances alpha-1 and alpha-3 glycine receptors
1. Opens chloride channels
2. Inhibitory
Enhances 5HT1a receptor activity
CBD
MECHANISMS
Vanilloid receptors
1. Large family of receptors that mostly mediate nociception for a
variety of stimuli
2. CBD mostly active at:
a. Inhibits Melastatin type 8 channel (TRPM8)
- cold nociception
b. Enhances transient receptor potential (TRP) ankyrin type 1 (TRPA1)
- cold nociception
c. Enhances TRP vanilloid type 1 (TRPV1)
- heat nociception (capsaicin example)
- can also mediate vasodilatation, bronchoconstriction
- may inhibit tumor cell growth and apoptosis
CBD
MECHANISMS
Inhibits equilibrium nucleoside transporter (ENT)
1. Transports nucleosides across cell membrane
2. Poorly understood
Activates nuclear peroxisome proliferator receptor gamma
1. Regulates gene expression (up or down)
2. Can have effects on nociception, immune system, metabolic
functions, neoplasia, GI system, CV system
Inhibits degradation of anandamide
CBD CLINICAL EFFECTSLIKELY EFFECTIVE
EPILEPSY
Epidiolex (cannabidiol)
1. FDA approved for Dravet and Lennox-Gastaut syndromes
a. Dravet
- 1:15,700 children
- Seizures begin first year of life; frequent and long myoclonic,
hemiclonic, GTC
- Generally poor response to first line anticonvulsants
- Most common cause is a sodium channel mutation (SCN1A)
- Total seizure frequency decreased by 39% vs 13% for placebo
CBD CLINICAL EFFECTSLIKELY EFFECTIVE
EPILEPSY
Epidiolex® (cannabidiol)
1. FDA approved for Dravet and Lennox-Gastaut syndromes
b. Lennox-Gastaut
- 0.1 – 0.28/100,000
- Begins age 3-5 with multiple generalized seizure types; tonic, atonic, atypical absence
- often poor response to first line anticonvulsants
- numerous causes but all produce widespread CNS damage/dysfunction
- Total seizure frequency decreased by 36-41% vs 14-18% for placebo
2. Efficacy signal in small numbers of other types of refractory seizure disorders
Possible mechanisms include ENT, GPR55, TRPV1, Glycine receptors, 5HT1a
DS Clinical Trial Results
LGS Clinical Trial Results
LGS Clinical Trial Results
CBD CLINICAL EFFECTSINSUFFICIENT RELIABLE EVIDENCE TO RATE
CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS
Dystonia1. 100-600 mg daily for 6 weeks produced 20-50% improvement in
dystonia from Meige syndrome, L-Dopa, and primary dystonia
2. No controlled studies
3. Unclear mechanisms
Parkinson disease1. Flexible dose of at least 150 mg daily for 4 weeks improved
psychosis
2. No controls
3. May worsen bradykinesia and tremor
4. Mechanisms unclear
CBD CLINICAL EFFECTSINSUFFICIENT RELIABLE EVIDENCE TO RATE
CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS
Huntington Disease
- 10 mg/kg/day did not improve chorea or other symptoms
compared to placebo
Multiple Sclerosis
1. 120 mg/day might improve self reported pain and muscle spasm
severity
2. No improvement in muscle spasm frequency, fatigue, bladder
control, mobility, QoL
3. No improvement in Ashworth scale
4. Some in vivo and in vitro work suggests CBD modulates immune
system function but no clinical effect seen in MS to date
CBD CLINICAL EFFECTSINSUFFICIENT RELIABLE EVIDENCE TO RATE
CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS
Schizophrenia1. One positive study at 400 mg QID for 4 weeks
2. Other studies negative but different doses and duration
3. Mechanisms: Anandamide, TPRV1, 5HT1a
Addictive Behaviors- May decrease cue-induced drug seeking behavior
Anxiety/Social Phobia1. Negative at 300 mg/day
2. At 400-600 mg/day anxiety improved vs placebo
3. Imaging showed decreased activity in left temporal lobe and amygdala
4. Mechanisms: 5HT1a, TPRV1 (vanilloid) channels
CBD CLINICAL EFFECTSINSUFFICIENT RELIABLE EVIDENCE TO RATE
CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS
Depression
1. Animal studies favorable
2. Mechanism: 5HT1a
Bipolar Disorder
1. 600-1200 mg/day for 25 days did not improve manic episodes
2. Case reports mostly
CBD CLINICAL EFFECTSINSUFFICIENT RELIABLE EVIDENCE TO RATE
CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS
Insomnia
1. 160 mg before bed improved sleep duration (but not 40 or
80 mg) compared to placebo
2. No effect on sleep onset latency
3. No morning hangover
4. Mechanism unclear
CBD CLINICAL EFFECTSINSUFFICIENT RELIABLE EVIDENCE TO RATE
CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS
Crohn’s Disease
- 10 mg SL BID for 8 weeks did not improve disease activity or CRP
Type II Diabetes
- 100 mg BID for 13 weeks did not improve lipid levels, glucose or
inflammatory markers
Graft vs Host Disease (GVHD)
1. 150 mg BID for 5-6 weeks delayed GVHD prior to day 100 but not at 12 months
2. Not clear if longer treatment duration would further delay GVHD
CBD CLINICAL EFFECTSINSUFFICIENT RELIABLE EVIDENCE TO RATE
CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS
Anti-Tumor Effects
1. No human studies
2. Cell culture studies show inhibition of malignant cell proliferation,
inhibition of invasion and metastasis, and decreased tumor mass
3. Mechanisms unclear
CBD CLINICAL EFFECTSINSUFFICIENT RELIABLE EVIDENCE TO RATE
CELL CULTURE, ANIMAL MODELS, CASE SERIES, SMALL NUMBERS
Pain
1. Recent review in PAIN (October 2018)
a. Pooled 104 RCT and observational studies of cannabanoids in chronic non-cancer pain
b. 29.0% vs 25.9% (placebo) for 30% reduction in pain (p<0.05)
- NNTB: 24
c. 18.2% vs 14.4% (placebo) for 50% reduction in pain (p>0.05)
d. 18.9% vs 11.8% (placebo) for patient global impression of change (p<0.05)
- NNTB: 38
e. 81.2% vs 66.2% (placebo) for all AE’s
- NNTH: 6
f. 15.8% vs 4.6% (placebo) for AE’s leading to study withdrawal
- NNTH: 40
CBD
Pharmacokinetics
1. Bioavailability
a. Oral: 13-19%
b. Inhaled: 11-45%
2. Half-life
- 18-32 hours
3. Excretion
- in urine, either unchanged or as glucuronide metabolite
or
mostly in feces
CBD
Formulations
1. Capsules
2. Sublingual spray
3. Oil based solution
Dosing
1. Data best for Epidiolex (oil based solution)
a. Usually 5-20 mg/kg/day for epilepsy
b. Doses as high as 50 mg/kg/day have been used
2. BIG problems with other commercially available products
The Trouble with CBD Oil
• Epidiolex (cannabidiol) unlikely to be
approved for “off-label” usage
• CBD content in over the counter CBD oil is
unpredictable
• Possible THC contamination
• Other contamination- Fertilizer,
pesticides ect.
CBD Toxicology
1. LD50 for IV is 212 mg/kg
2. LD50 for oral route not established but likely 20-50X that for IV
Adverse Effects (appear dose related)1. Dry mouth
2. Diarrhea
3. Vomiting
4. Decreased appetite
5. Weight loss
6. Somnolence
7. Fatigue
8. Elevated liver transaminases
CBD
Drug Interactions
1. CYP2C19 Substrates
a. Clobazam (ONFI) - major
b. Topiramate – major
c. Interactions not significant for other anticonvulsants
2. Valproic Acid
a. Elevated liver transaminases
b. Thrombocytopenia
WHAT I LEARNED FROM THIS
There is at least one clinical use for CBD – epilepsy
VERY messy overall (this also makes it fun)
Strange situation – a drug in use for millennia just now being examined with basic science and clinical studies
- The political, social, and marketing campaigns only serve to worsen the confusion
We need better dose-response data for the various illnesses being investigated
We need formulations of CBD whose composition we can be confident about
Make it Schedule II?
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Neurochem Res. 2005 Aug;30(8):1037-43
Neuropharmacology. 2018 May 1;133:224-232. doi: 10.1016/j.neuropharm.2018.01.041. Epub 2018 Feb 1.
Epilepsia, 55(6):787–790, 2014
Journal of Pharmacology and Experimental Therapeutics June 2008, 325 (3) 1007-1015
Int. J. Mol. Sci. 2018, 19(11), 3320
Br J Pharmacol. 2016 Jun; 173(12): 1899–1910.
Curr Neuropharmacol. 2006 Jan; 4(1): 1–15.
Curr Med Chem. 2010; 17(14): 1468–1486.
Transl Psychiatry. 2012 Mar; 2(3)
National Academies of Sciences, Engineering, and Medicine. 2017. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press. https://doi.org/10.17226/24625.
https://naturalmedicines-therapeuticresearch-com.offcampus.lib.washington.edu/databases/food,-herbs-supplements/professional.aspx?productid=1439