CBD and the Endocannabinoid System OBJECTIVES Gain understanding - - PowerPoint PPT Presentation

CBD and the Endocannabinoid System

OBJECTIVES

• Gain understanding of cannabinoid system in

the human body

• What is CBD
• Neurobiology of CBD
• Clinical evidence for CBD use
• CBD and Addiction Issues

I have heard that CBC oil helps with stress and

• insomnia. Is it OK if I try it?

What are Cannabinoids?

• Diverse group of chemical compounds that act
• n cannabinoid receptors (endocannabinoid

system)

• Endocannabinoids (2 major)
• Phytocannabinoids ( > 100 )
• Synthetic cannabinoids (Spice, K2)

Phytocannibinoids

ENDOCANNIBINOID SYSTEM

• Endocannabinoids (AEA and 2-AG)
• Receptors for the endocannabinoids

CB1 , CB2

• Enzymes responsible for production and

degradation of the endocannabinoids

The Endocannabinoids

• AEA is a high affinity, partial agonist of the CB1 and almost

inactive at the CB2 receptors

• 2-AG acts as a full agonist at both CB1 and CBD2 with moderate to

low affinity

• Endocannabinoids are arachidonic acid derivatives

synthesized on demand in the post synaptic terminals

• Serve as the breaking system in our brains
• They are rapidly broken down (unlike THC and exogenous)

CB1 CB2 2-AG Ananadamide

Where are CB1 receptors located ?

CB1R receptor

• Also expressed in the peripheral nervous system
• Mostly expressed in sympathetic nerve terminals,

trigeminal ganglion, dorsal root ganglion, and sensory neurons where it regulars nociception from afferent nerve fibers

• In GI tract CB1 s enriched in both the enteric nervous

system and in non-neuronal cells in the intestinal mucosa, enteroendocrine cells, immune cells and

• enterocytes. It modulates the mobility of the GI tract,

the secretion of gastric acids, fluids, neurotransmitters and permeability of the intestinal epithelium.

• Normally expression of CB1 is low in the liver

CB2 EXPRESSION

• CB2- primarily located peripheral tissues and

immune cells (B cells, T cells, monocytes, macrophages) where they influence the release

• f cytokines
• A moderate expression in other peripheral tissues

including the cardiovascular system, GI tract, liver, adipose tissue, bone and reproductive system

• Regulates a number of important cellular

processes in mature and developing tissue such as immune suppression, induction of apoptosis, migration of inflammatory cells

Physiological roles

• Given their widespread distribution the

endocanniboid system is involved in appetite, learning and memory, anxiety, depression, schizophrenia, stroke, MS, neurodegenerative diseases, epilepsy, and addiction.

• Peripherally pain, energy metabolism,

cardiovascular and reproductive functions, inflammation, glaucoma, cancer, liver and musculoskeletal disorders

KNOCK OUT MICE

• Lack the gene to make CB1 receptor
• Are lean ( 24% less body wt. and 60% less

body fat)

• Increased brain inflammation
• Increased aggression / anxiety
• Higher mortality rates
• Attenuated reward behaviors

The story of rimonabant

CBD (Cannabidiol )

• No CBD receptor found yet
• Low receptor affinity for CB1 and CB2
• Acts as an blocker (inverse agonist) of THC, at

concentrations well below the reported affinity for THC

• Modulate the activity of many cellular effectors

including CB1 , CB2, 5HT1A, GPR55, GRP18 TRPV1, FAAH

• In the presence of THC it antagonizes the CB1

(regulates the negative effects of THC such as anxiety, tachycardia, sedation and hunger)

CBD and the immune system

• In the murine model of lipopolysaccharide

induced acute lung injury, microglial cells,

• decreases neutrophil, macrophage and

lymphocyte migration

• decreases myeloperoxidases activity in tissue
• decreased production of inflammatory

cytokines, TNF-alpha, IL-6, chemokines

Biological effects of CBD

WHAT ABOUT DOING SOME EXPERIMENTS IN HUMANS

RCTs with CBD

• 35 clinical trials involving CBT covering 13

medical conditions

• 23 reported positive outcomes, 12 negative
• Total of 1223 participants
• 15 RCT
• 8 clinical trials (open label trials)
• 12 care reports, series

RCTs with CBD

• 4 seizures disorders (positive)
• 3 schizophrenia (positive)
• 1 generalized anxiety disorder (positive)
• 1 Parkinson's (positive)
• 1 Huntington's (negative)
• 1 chronic pain (negative)
• 1 glaucoma (negative)
• 1 fatty liver (negative)
• 1 diabetes (negative)

• Double blind placebo study
• 36 patients (24 with social anxiety disorder and 12 without) randomized to

CBD (600mg) or placebo

• Stimulated public speaking test, analogue measures of anxiety

Cannabidiol Reduces the Anxiety Induced by Stimulated Public Speaking in Treatment-Naice Social Phobia Patients, Bergamaschi M., et al, Neuropsychopharmacology 2011 May; 36(6) 121901226

Inverted U-Shaped Dose –Response Curive of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life: Zuardi AW., et al. Front Pharmacol 2017 May 11;8:259

Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial; McGuire P, et al; Am J Psychiatry March 2018; 175 (3)

• Double –blind parallel- trial
• 43 CBD, 45 Placebo
• 1000mg CBD daily
• Various Scales including the

PANSS (Positive and negative syndrome scale)

• 2 withdrawals due to side

effects

• No change in the negative

scores

CBD as a pharmaceutical medical agent

• Epidiolex (GW Pharmaceuticals, UK) treatment resistant

seizures Arvisol (Echo Pharmaceuticals, Netherlands) schizophrenia, seizures CBD gel (Zynerba Pharmaceuticals) Fragile X syndrome, seizures Bionorica (THC Pharm) Germnay INSYS Pharmaceuticals (US)- seizures, infantile spasms, anxiety Ananada Scientific (Israel)

• Currently at least 49 ongoing clinical trials

CBD product sales

• 2018 Farm Bill Act legalized hemp (< 0.3% THC) production and

declassifies hemp as a Schedule I controlled substance and removed it from the CSA. Becomes an agricultural commodity.

• Marijuana plants (> 0.3%) remain a schedule I and under the

CSA/DEA

• CBD was not addressed in the Farm Bill , it did state that any

cannabinoid derived from hemp is legal if produced in a manner consistent with the farm bill.

• Shifted its regulation from the DEA to the US Department of

Agriculture

• However it preserved the FDA authority to regulate products

containing cannabis derived products

• FDA regulates cannabis products under the Food, Drug and

Cosmetic Act of Public Health Service Act. Any cannabis product marketed with a claim of therapeutic benefit must be approved by the FDA before it can be sold.

• The FDA identifies 3 lawful hemp products (hulled hemp seeds,

hemp seed protein and hemp seed oil). These products can be marketed legally if sold without claiming therapeutic benefit.

• Currently there are no FDA approved CBD products besides 3

medical agents that contain THC/CBD. CBD is illegal from the FDAs standpoint.

• There are no standards for production

Indiana Senate Bill 52

• Legalized CBD as a commercial product
• Must be < 0.3% THC
• Packaging must contain a scannable bar code that links to a

document that contains information regarding batch, certificate of analysis of low THC hemp content

• IS IT SAFE?
• IS IT EFFECTIVE?
• WILL IT IMPACT SOBRIETY?
• WILL IT SHOW UP IN URINE AS THC

Production of CBD oil

• CBD oil is made from the most of the Hemp plant which

contain the highest levels of CBD and concentrates the CBD

• Hemp (seed) oil is pressed from the seeds of the Hemp plant

does not contain significant amounts of CBD or THC

How is it produced

• The actual production of the plant is regulated by the

Department of Agriculture and state laws.

• Indiana set up requirement for hemp license, an advisory

board and monitoring by the state seed commissioner.

• A sample of each crop is tested by the state and farmers

are only allowed to use seeds or clones provided by certified research institutions

Hazelkamp A, Epifanova S; Grote variatie in samnestelling cannabisolie noopt tot regels. Pharmaiceutisch Weekblad 2017;152:16-18

Is it safe

CBD as a pharmaceutical medical agent

• Epidiolex (GW Pharmaceuticals, UK) treatment

resistant seizures

• Maximal dose 10mg/kg BID ( 1500mg)
• Adverse reactions

30%- drowsiness, lethargy, sedation 11%- insomnia 20%- decreased appetite and diarrhea 30%- anemia 15% increased liver tests >3x 25-40% infection

• Drug interactions

What is the right dose

• Little information on bioavailability
• 15 RCTs
• Dose ranges from < 1mg/kg up to 20mg/kg

average 9mg/kg

• 7 + studies average dose 14mg/kg
• 7 – studies average dose 5mg/kg

Drug – Drug Interactions

• CBD is metabolized by CYP3A4 enzyme
• Inhibitors of this enzyme include

ketoconazole, itraconazole, ritonavir and clarithromycin

• Inducers of this enzyme include

phenobarbital, rifampin. Carbamazepine and phenytoin

Addiction potential

• The World Health Organization Expert

Committee on Drug Dependence concluded there is no evidence for dependency or Abuse potential

CBD in the treatment of addiction?

• Recent study in American Journal of psychiatry
• Goal was to evaluate CBD in reducing cue-

induced craving and anxiety

• Double –blind randomized placebo controlled

trail

Cannabidiol for the Reduction

• f Cue-Induced Cravings and

Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo- Controlled Trial: Hurd Y., et al; Am J Psychiatry 2019 Nov 1; 176(11):911-922

CBD and urine drug tests

• No data on the various manners of CBD

ingestion

• At usual consumption of CBD products, if

<0.3% THC, urine drug screen cut offs would not be obtained

• However with confirmation tests values < 50

could be possible.

Conclusions

• CBD has significant potential as a pharmacologic agent, in

both medical and mental health

• However many of the current claims are overstated if not just

incorrect

• It appears to be safe but can have side effects at high doses
• We don’t know the effective dosing
• It is not addicting. Studies needed on effect on relapse and

recovery.

• It will probably be years before we see it as a pharmacological

agent so the wild west will not be tamed

I have heard that CBC oil helps with stress and

• insomnia. Is it OK if I try it?