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 on 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 derivativessynthesized on demand in the post synapticterminals

• 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 of 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 negativesyndrome 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 seizuresArvisol (Echo Pharmaceuticals, Netherlands) schizophrenia, seizures CBD gel (Zynerba Pharmaceuticals) Fragile X syndrome, seizuresBionorica (THC Pharm) GermnayINSYS Pharmaceuticals (US)- seizures, infantile spasms, anxietyAnanada 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, sedation11%- insomnia20%- decreased appetite and diarrhea30%- anemia15% increased liver tests >3x25-40% 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 includephenobarbital, 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 of 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?