Physiology of the

Endogenous Cannabinoid

systemSara Jane Ward, PhD

Assistant Professor of Pharmacology

Center for Substance Abuse Research

Temple University Lewis Katz School of Medicine

Adjunct Professor

Medical Cannabis Certificate Program

Institute of Emerging Health Professions at

Thomas Jefferson University

Medical, Scientific, and Legal History

10,000 – 5,000 BC

CENTRAL ASIA

Cannabis plant

domesticated for

source of fiber

(hemp rope) and

nutrition (seed)

~ 3000 BCUS, ISRAEL

CBD, Δ9THC

isolated and

studied

1940-60’s

WASHINGTON DC

Marihuana Tax Act

US

Companies like

Lilly and Parke

Davis sell Cannabis

extract as

medicine

CHINA, INDIA

Cannabis used for

medicinal and

recreational

purposes1910-20s

1937 1970

US

Passage of the

Controlled

Substances Act

WM O’SHAUGHNESSY

Brought Cannabis to

western medicine from

India, first scientist to

test in animals and

humans

1800s AD

Cannabis Sativa

• One of the oldest plants known to man (~4000 BC)

• Phytocannabinoids (>100) are a specific chemical class found in Cannabis sativa

• Found in highest concentration in the resin secreted by female plants

• Most abundant CBs found in Cannabis Sativa• THC• Cannabidiol (CBD)

• THCA and CBDA • Cannabinol (CBN)• Cannabichromene (CBC)

• Cannabigerol (CBG)• Cannabivarin (CBV)• Cannabidivarin (CBDV)

• Also pharmacologically active terpenes, flavonoids, etc…

Hemp

• Hemp is a classification of Cannabis sativa that was cultivated primarily for agricultural use (~2800 BCE)

• Described as non-intoxicating, containing < 0.3% THC

• Now re-popularized as a source of CBD

• Under the 2018 US Farm Bill Hemp and its extracts are decoupled from “Marijuana” under the controlled substances act

Medical, Scientific, and Legal History

10,000 – 5,000 BC

CENTRAL ASIA

Cannabis plant

domesticated for

source of fiber

(hemp rope) and

nutrition (seed)

~ 3000 BCUS, ISRAEL

CBD, Δ9THC

isolated and

studied

1940-60’s

WASHINGTON DC

Marihuana Tax Act

American

Pharmacopeia

Used widely as an

analgesic,

antispasmodic, and

sedative

CHINA, INDIA

Cannabis used for

medicinal and

recreational

purposes1850-1941

1937 1970

US

Passage of the

Controlled

Substances Act

WM O’SHAUGHNESSY

Brought Cannabis to

western medicine from

India, first scientist to test

in animals and humans

1800s AD

Medical, Scientific, and Legal History

10,000 – 5,000 BC

CENTRAL ASIA

Cannabis plant

domesticated for

source of fiber

(hemp rope) and

nutrition (seed)

~ 3000 BCUS, ISRAEL

CBD, Δ9THC

isolated and

studied

1940-60’s

WASHINGTON DC

Marihuana Tax Act

American

Pharmacopeia

Used widely as an

analgesic,

antispasmodic, and

sedative

CHINA, INDIA

Cannabis used for

medicinal and

recreational

purposes1850-1941

1937 1970

US

Passage of the

Controlled

Substances Act

WM O’SHAUGHNESSY

Brought Cannabis to

western medicine from

India, first scientist to test

in animals and humans

1800s AD

The American Medical Association opposed the act because the tax was

imposed on physicians prescribing cannabis, retail pharmacists selling

cannabis, and medical cannabis cultivation/manufacturing. Leaders of the

AMA also did not believe the propaganda surrounding cannabis and

criticized the use of the term “marijuana”

Medical, Scientific, and Legal History

10,000 – 5,000 BC

CENTRAL ASIA

Cannabis plant

domesticated for

source of fiber

(hemp rope) and

nutrition (seed)

~ 3000 BCUS, ISRAEL

CBD, Δ9THC isolated

and studied

THC identified as the

“psychoactive”

cannabinoid

Antiseizure properties

of both molecules

described

1940-70’sWASHINGTON DC

Marihuana Tax Act

American

Pharmacopeia

Used widely as an

analgesic,

antispasmodic, and

sedative

CHINA, INDIA

Cannabis used for

medicinal and

recreational

purposes1850-1941

1937 1970

US

Passage of the

Controlled

Substances Act

WM O’SHAUGHNESSY

Brought Cannabis to

western medicine from

India, first scientist to test

in animals and humans

1800s AD

Medical, Scientific, and Legal History

10,000 – 5,000 BC

CENTRAL ASIA

Cannabis plant

domesticated for

source of fiber

(hemp rope) and

nutrition (seed)

~ 3000 BCUS, ISRAEL

CBD, Δ9THC isolated and

studied

Antiseizure properties

of both molecules

described

1940-

70’s

WASHINGTON DC

Marihuana Tax Act

American

Pharmacopeia

Used widely as an

analgesic,

antispasmodic, and

sedative

CHINA, INDIA

Cannabis used for

medicinal and

recreational

purposes1850-1941

1937 1970

US

Passage of the

Controlled

Substances Act

WM O’SHAUGHNESSY

Brought Cannabis to

western medicine from

India, first scientist to test

in animals and humans

1800s AD

Potential for Abuse Accepted Medical Use? Potential for Addiction

Schedule I(Heroin, Cannabis, LSD…)

High NoneDrug is not safe to use, even under medical supervision

Schedule II(Cocaine, Morphine,barbiturates…)

HighYes; sometimes allowedonly with "severe restrictions"

Abusing the drug can cause severe physical and mental addiction

Schedule III(Anabolic Steroids, Ketamine, Marinol…)

Medium Yes

Abusing the drug can cause severe mental addiction, or moderate physical addiction

Schedule IV (Benzos,tramadol)

Low YesAbusing the drug may lead to mild mental or physical addiction

Schedule V (Pregabalin, Epidiolex…)

Lowest YesAbusing the drug may lead to mild mental or physical addiction

1980’s - National Cancer Institute, FDA, and Unimed

Marinol- Schedule III - THC encapsulated in sesame oil - approved by the FDA in 1985 for the

treatment of nausea and vomiting associated with cancer chemotherapy

THC synthesized in a lab

Schedule III

THC “analogue”

Schedule II

Medical, Scientific, and Legal History

Discovery of the endocannabinoid system

The eCB system

• Two confirmed receptor subtypes, many other putative• CB1 ubiquitous in MANY TISSUE TYPES, perhaps most abundant GPCR in nervous

tissue• CB2 more localized, e.g. on cells involved in immune function• THC binds equally to both, CBD BINDS TO NEITHER

• Two confirmed endogenous ligands (eCBs), anandamide and 2-AG, many other putative• Cleaved by lipid precursors on demand• Degraded by at least two enzymes

Modern-day Medical Cannabis and Cannabidiol in the US

Hemp Farming Act of 2018

December 2018 – Hemp

extracts with <0.3% THC are

removed from Schedule I

designation

NJ approved indications

Cannabidiol• Identified in the US in the 1940s

• Devoid of most “psychoactive” effects

• Anti-seizure effects reported in 1973

• Other successful human studies: Anxiety, Schizophernia

• Epidiolex FDA approved June 2018 – Schedule V

• Majority of clinical evidence for other indications is anecdotal

• Mechanism(s) unclear, Poor PK, bioavailability, Liver toxicity

• Hemp Farming Act of 2018 legalizes hemp-based CBD at the federal level

• <0.3% THC

• Predicted CBD sales $22 billion by 2022

• Mainly OTC through national retail chains

• Serious issues surrounding reliability of products

Putative mechanisms

of action

General cannabinoid pharmacology • Most of what we know comes from 1) animal studies 2) chronic

recreational use, and 3) relatively fewer controlled clinical studies

• At least two meta-analyses summarize that cannabinoid-based treatments show effectiveness for the treatment of chronic pain and spasticity (Whiting et al JAMA 2015; NASEM 2017; also see https://nccih.nih.gov/health/marijuana-cannabinoids#refs

• Low quality evidence for other indications, e.g. nausea, sleep disturbances, anxiety

• Increased risk of short-term mild to moderate adverse events

• Effects are dose, composition (THC, CBD etc), and frequency of use dependent

• Based on the localization and relative expression of CB1, CB2, and other cannabinoid targets, systemic administration of Cannabis can produce potential beneficial and/or adverse effects on many tissues and organ systems

Cannabinoids and CNS pharmacology

ECS regulation

• eCB present throughout

• Some alterations present w/ pathology

• Neurotransmission

• Stress

• Analgesia

• Appetite

• Injury/inflammation

• Hormonal function

Effects of Cannabis/Cannabinoids

• THC – altered sensation, perception, mood (euphoria *CUD, anxiety *bidirectional, psychosis), cognition, sedation, emesis

• CBD – anxiolysis, sedation

• Sativex trials give some additional information re: adverse effects of medical use

• Potential therapeutic effects of Cannabis:

• analgesia, nausea and vomiting, neuro-inflammation, neuro-protection, PTSD?

• CBD – antiseizure, anticonvulsant, anxiolytic, sleep disturbances, anti-antipsychotic, autism?

Cannabinoids and GIpharmacology

ECS regulation

• eCB present throughout

• Some alterations present w/ pathology

• GI secretion

• GI motility

Effects of Cannabis/Cannabinoids

• THC – gut motility, no adverse GI effects yet noted (see below)

• Potential therapeutic effects of Cannabis:

• anti-emetic (but can be pro-emetic in CHS), GERD, IBD? antispasmodic

• CBD – anti-inflammatory, IBD?

Cannabinoids and liverpharmacology

ECS regulation

• eCS present throughout at levels comparable to CNS

• eCS levels are elevated with several hepatic pathologies

• CB2 system may monitor inflammation

• CB1 activation may promote disease

Effects of Cannabis/Cannabinoids

• Recreational use not associated with liver pathology, possible due to opposing roles of CB1 and CB2

• Potential therapeutic effects of cannabinoids:

• CB2 receptor activation may be therapeutic

• CB1 receptor BLOCKADE also a target

• CBD is associated with hepatotoxicity

Cannabinoids and Cardiovascularpharmacology

ECS regulation

• Cannabinoid receptors are located in the myocardium, vascular endothelial and smooth muscle cells, as well as circulating blood cells

• CB1R are also present in the peripheral nervous system, including vagal afferent neurons, and can modulate cardiovascular function

• While Cannabis can decrease blood pressure, the eCS appears to play no homeostatic role here

• CB2 system associated with protective effects

• CB1 activation may promote disease

Effects of Cannabis/Cannabinoids• 2016 WHO report includes adverse

cardiovascular effects as a potential harmful health consequence of cannabis use

• States that a likely factor is increase in THC content from around 2-3% up to 20% over the past decades

• A growing number of case reports and clinical studies associate recreational cannabis use with adverse cardiovascular consequences ranging from acute coronary syndrome; coronary thrombosis; myocardial infarction; cardiomyopathies; heart failure; stroke; vasospasm, vascular inflammation, or artery dissection; arrhythmias (atrial fibrillation, atrioventricular block, ventricular tachycardia or fibrillation, asystole), and sudden death

• Potential therapeutic effects of cannabinoids:• CB2 receptor activation may be

therapeutic• CB1 receptor BLOCKADE also a target• CBD may be cardioprotective

Other physiological/

pharmacological effects of

interest

Potential therapeutic:

Arthritis – pain or disease modifying

Other autoimmune indications

Opioid use disorders

Other potential adverse effects:

Reproductive

Gestational

ACKNOWLEDGEMENTS

• Co-Investigators

• Ellen Walker, PhD

• Harshini Neelakantan, PhD

• Ronald Tuma, PhD

• Ronald Tallarida PhD

• Ward Laboratory

• Hongbo Li, MD, PhD

• Jeff Foss MS

• Dan Farkas

• California Pacific Medical Center

• Research Institute

• Sean McAllister, PhD

• KANNALIFE

• Bill Kinney, PhD

• Doug Brenneman, PhD

• Funding:

• R03 National Institutes of Health (SJW)

• INSYS Rx INC (SJW)

• NIDA STTR (DB, SJW)