cannabidiol (cbd) the be all end all?€¦ · cbd clinical effects likely effective epilepsy...

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?

REFERENCES Nucleosides Nucleotides Nucleic Acids. 2017 Jan 2; 36(1): 7–30.

J Med Chem. 2016 Nov 23;59(22):10006-10029. Epub 2016 Aug 1.

Neurology April 10, 2018; 90 (15 Supplement)

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