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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)
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