Marijuana

Aron H. Lichtman
Professor
Department of Pharmacology and Toxicology
 Learning Objectives
1. Be familiar with the primary constituents of marijuana
2. Learn the complex pharmacological properties of
cannabinoids
3. Be able to discuss pros and cons of medical marijuana
4. Know approved and potential uses of cannabinoid-based
medications
5. Know the adverse effects of cannabinods
6. Understand the general mechanism of action underlying
marijuanas pharmacological effects
7. Identify the key components of the endogenous
cannabinoid system
8. Understand the putative physiological roles of the
endogenous cannabinoid system
 I. What are Cannabinoids?

Answer:
Diverse drug class of differing chemical structures
Present in brains and bodies of
originally discovered in humans and other animals
marijuana

Synthesized by chemists
 Chemical constituents
Chemical classes
Cannabinoids (100+) of cannabis
Nitrogenous cmpds (27)
Amino acids(18) OH
Proteins/ enzymes (11)
Sugars (34)
Hydrocarbons (50) O
Simple alcohols (7)
THC
Simple aldehydes (12)
Simple ketones (13)
Simple acids (21)
Fatty acids (22)
Simple esters/lactones (13)
Steroids (11)
Terpenes (20)
Non-cannabinoid phenols (25)
Flavoroids (21)
Vitamins (1)
Pigments (2)
Elements (9)
Total known compounds (483)
 Gaoni and Mechoulam (1964)*
Elucidated the Structure of THC

*Journal of the American Chemical Society, 86:1646-47

 Cannabidiol

Mechoulam and Shvo (1963) Hashish. I. The

structure of cannabidiol, Tetrahedron
19(12):2073-8.
Most Adults Have Smoked Marijuana

http://www.monitoringthefuture.org/
Marijuana Use in Young Adults: Annual

http://www.monitoringthefuture.org/
Marijuana Use in Young Adults: Daily

http://www.monitoringthefuture.org/
 Discussion

Given that so many people smoke

marijuana, is it a safe drug?
 Concerns
Associated with schizophrenia
Impaired driving
Large number of emergency room visits
Impairs memory
Dependence
High THC content in Marijuana
Co-morbidities (anxiety and depression disorders)
Legal/socioeconomic hindrance
Survey of intoxication and driving accidents*

6.8% of drivers (mostly under 35), who were

involved in accidents tested positive for THC

21% of these drivers involved in accidents

were above the legal limit for alcohol levels

*http://www.nida.nih.gov/ResearchReports/Ma
rijuana/marijuana4.html#driving
It is illegal for anyone to possess Cannabis
sativa and its products and constituents -
signatories of WHO Convention

Therefore, how is it possible for the

scientific community to conduct scientific
experiments with the Cannabis sativa?
Source of Marijuana - NIH
Sponsored Mississippi Farm
 Chemical constituents of
Chemical classes
Cannabinoids (100+)Cannabis sativa
Nitrogenous cmpds (27)
Amino acids(18) OH
Proteins/ enzymes (11)
Sugars (34)
Hydrocarbons (50) O
Simple alcohols (7)
THC
Simple aldehydes (12)
Simple ketones (13)
Simple acids (21)
Fatty acids (22)
Simple esters/lactones (13)
Steroids (11)
Terpenes (20)
Non-cannabinoid phenols (25)
Flavoroids (21)
Vitamins (1)
Pigments (2)
Elements (9)
Total known compounds (483)
 Marijuana Constituents:
Cannabinoid Structures
11
CH3 CH3 CH3
9
8 OH OH OH
10a 1
6a
3
O O HO

THC Cannabinol Cannabidiol

1.0 0.1 0
(Psychoactivity index)

THC (tetrahydrocannabinol) identified in 1964

 Cannabis Constituents Summary
1. THC is the primary pharmacologically active constituent
2. Over 400 known chemicals
3. Over 100 cannabinoid compounds have been identified
4. High potency marijuana contains high quantities of THC
5. Marijuana potency has increased in recent years
6. Scientific community has legal access to marijuana and
THC
 Marijuana Intoxication in Humans

The high
Altered state of consciousness
Mild euphoria and relaxation
Perceptual alterations
Time distortion
Ordinary sensory experiences intensified
Increased sociability
Impaired cognition - memory recall
Altered motor function complex tasks
Pharmacological Properties in Humans:
Peripheral Effects
Heart rate increased (common effect)
Blood pressure generally unchanged
Orthostatic hypotension (high doses)
Conjunctival reddening
Decreased muscle strength (high doses)
Appetite/food intake increased (variable)
Anti-emesis
Reduction in intraocular pressure
Bronchodilation
 Pharmacological Effects of
Cannabinoids in Laboratory Animals
Increased heart rate
Ataxia
Tetrad
- Hypomotility
- Analgesia
- Catalepsy
- Hypothermia
Increased appetite
Diminished muscle tone
Discriminative cue
Self-administration
Memory disruption
 Discussion

Does marijuana use cause

physical dependence?
According to the 2008 NSDUH,
marijuana accounted for 4.2 million of
the estimated 7 million Americans
dependent on or abusing illicit drugs.

http://www.nida.nih.gov/PDF/RRMarijuana.pdf
In 2008, approximately 15 percent of
people entering drug abuse treatment
programs reported marijuana as their
primary drug of abuse

http://www.nida.nih.gov/PDF/RRMarijuana.pdf
 Abstinence Symptoms during
Marijuana Withdrawal
Anxiety
Irritability
Physical tension
Decreases in mood
Decreases in appetite
Sleep disturbances
Most pronounced for first 10 days, persisted
throughout 28-day abstinent period

Kouri and Pope, 2000

Consequences of Marijuana Dependence

High rate of remission based upon risk estimates and

number seeking treatment
Individual variability
Major complaints of those seeking treatment are:
loss of control over drug use
cognitive and motivational impairment
interferes with occupational performance
lowered self-esteem and depression
complaints from spouses and partners
 Animals Models Used to Investigate
Drug Abuse and Drug Dependence
Reinforcing Effects
Drug self-administration (generally difficult to demonstrate)
Conditioned place-preference (generally difficult to demonstrate)
Intracranial self-stimulation (generally difficult to demonstrate)
Sensitization (not well characterized)
Withdrawal (generally relies on antagonist precipitated models)
 D9-THC Is Self-
administered by Rhesus
Monkeys
OH

Justinova et al. (2003) Psychopharmacology, 169:135-40

II. Medicinal Cannabinoids

OH

O
 Discussion

Should the Food and Drug Administration (FDA) consider

approving the use of cannabis for medical purposes?
 The Paradox of Medical Marijuana
Marijuana Schedule I Substance
Under the Controlled Substances Act
possess high potential for abuse
no currently accepted medical use in treatment in the US
lack of accepted safety for use under medical supervision

Medical
wonder
Drug of
Abuse
Americans Favor Legalizing Marijuana for
Medical Purposes (Gallup Poll 2003)
States and Medical Marijuana

http://norml.org/laws/medical-marijuana-2
But Marijuana is a Schedule I Substance
Under the Controlled Substances Act

Schedule I drugs
possess high potential for abuse
no currently accepted medical use in treatment in the US
lack of accepted safety for use under medical supervision
 Abridged History: Medical Marijuana
2700 BC First recorded medical use of cannabis by Shen Nung one of the fathers of
Chinese medicine
550 BC Persian prophet Zoroaster writes the Zend-Avesta, a sacred text, which
includes cannabis as one of more than 10,000 medicinal plants
1840s Introduced into Western medicine
19th C-1937 Cannabis extracts listed in the USP
1985 FDA approves Marinol (dronabinol; oral D9-THC): antiemetic for cancer
chemotherapy
1991 FDA approves Marinol for cachaxia in AIDS patients
1990s-present States legalize medical marijuana
2005 Canada approves Sativex (sublingual D9-THC & CBD combination) for
relief of neuropathic pain in MS patients
2006 FDA approves Cesemat (nabilone) antiemetic for cancer chemotherapy
2006 EU approves Accomplia (rimonabant) for the treatment of obese patients
or overweight patients
2007 FDA special advisory committee rejects approval for rimonabant
2008 EU removes Accomplia from the market
2010 UK Medicines and Healthcare Products Regulatory Agency licensed Sativex
to treat spasticity due to Multiple Sclerosis
 Abridged Ancient History:
Medical Marijuana
2700 BC First recorded medical use of cannabis by Shen
Nung, a father of Chinese medicine
550 BC Persian prophet Zoroaster writes Zend-Avesta,
which includes cannabis as one of more than
10,000 medicinal plants

Photomicrographs of ancient cannabis

Russo E B et al. J. Exp. Bot. 2008;59:4171-4182
 Medical Marijuana
The Golden Age in Western Medicine
1840s Introduced into Western medicine
19th C-1937 Cannabis extracts listed in the USP
 Approved FDA Uses of Oral THC
Marinol (Dronabinol)
1) Antiemetic - for treatment of chemotherapy-induced
emesis (1985)
2) Appetite Stimulation cachexia, loss of appetite and
weight in AIDS patients (1991)

OH
FDA approved
Pure THC
Accurate doses
O
Clinically proven
Synthetic THC-like (Cannabinoid) Drug Approved
to Treat Nausea and Vomiting: Nabilone
(Cesamet)

nabilone
 Sativex
(Approved in Canada, UK, Europe, New Zealand)

THC

+
CBD

Clinical Uses
spasticity and pain due to multiple sclerosis
cancer pain
 Potential Therapeutic Uses of Cannabinoids
Cancer chemotherapy-induced
nausea & emesis
Appetite increase in AIDS and
cancer patients
Metabolic syndrome & weight loss
(antagonists)
Pain and Inflammation
Rheumatoid arthritis
Spinal/Neuropathic
Cancer/chemotherapy
Migraine
Pruritus (itching)
Palliative (quality of life)
Epilepsy (CBD)
Drug abuse disorders
Cannabis
Nicotine
Opioid
Cocaine
Psychiatric diseases
Anxiety disorders
Posttraumatic Stress Disorder
Depression
Neurodegenerative diseases
Spasticity/multiple sclerosis
Huntingtons disease
Parkinson's disease
Alzheimers disease
Amyotrophic lateral sclerosis
 Cannabinoid Receptor Agonists: Side Effects
Marijuana-like pharmacological effects
Motor deficits
Cognitive deficits
Perceptual alterations
Potential Psychiatric Conditions
Schizophrenia
Panic reactions
Abuse potential
Dependence potential
Bad PR
 Given the Availability of Oral THC and
Nabilone, Why Does the Public Support
Medical Marijuana?

1) Not aware of alternatives

2) Taking oral medications for nausea is unpalatable
3) Smoking more efficacious than oral THC
4) Faster onset of action than oral THC
5) Avoids first pass metabolism
6) Dose can readily controlled to limit side effects
7) Other marijuana constituents may also have therapeutic
effects
Arguments Against Medical Marijuana
1) Alternatives available in pipeline
2) Quality control issues (e.g., presence of fungi,
difficulty to control ingredients)
3) Difficult to provide accurate dosing
4) Untoward side effects (panic related disorders,
schizophrenia)
5) Increased illicit use
6) Abuse and dependence potential
7) Presence of carcinogens in marijuana smoke
8) Unlikely to ever receive FDA approval
9) Crime associated with growing & distribution
10) Contrary to principles of modern medicine
 Foxglove
Willow Tree Digitalis purpurea
Salix Medicine: digitalis
Medicine: salicylic acid

Opium
Marijuana Lachryma papaveris
Cannabis sativa Medicine: Morphine, codeine
Medicine: THC
Alternatives to Medical Marijuana and
Oral Cannabinoids
Deliver THC through other routes of administration
(inhalation, suppository, or transdermal)
a) no impurities
b) rapid onset (inhalation)
c) avoids first pass metabolism
d) accurate dose
e) dose can be readily titrated to limit sides
Other cannabinoid-based medications (decrease
psychoactive effects)
 D9-THC Metered Dose Inhaler
US Patent #s 6,713,048 and 6,509,005

1) no impurities
2) rapid onset
3) avoids first pass
metabolism
4) accurate dosing
5) dose can be easily titrated
to limit sides
Challenges
1. Technological (too many puffs needed)
2. High cost of drug development ($800 million to nearly $2 billion
per drug).
3. Industry reluctance to develop cannabimimetic drugs
 III. Endogenous Cannabinoid System

Challenges of elucidating mechanism of action

1. Marijuana and THC have complex pharmacological

profiles
2. Both substances produce a myriad effects in
biological systems
3. Physical characteristics of both substances make them
challenging to study
Early Hypothesis: Membrane Perturbation

OH

THC

OH

Lawrence & Gill (1975)

O
 Structure Activity Relationship

CH
3

OH

Unique effects O

Highly potent
Structural requirements
Structurally Diverse Drugs Produce THC-
like Effects
OH

O
O
CH3
THC
N
OH
O
OH N

WIN 55,212
OH
CP 55,940 O
OH
N
H

Anandamide
 CB1 Receptors

CB1

Adipose Muscle Liver GI Pancreas

Tissue Tract

Brain
Responsible for most of CNS marijuana effects

Devane et al. (1988) Mol Pharm, 34:605-613

Herkenham et al (1990) PNAS,87:1932-1936
Matsuda et al. (1990) Nature, 346: 561-4
 Brain Regions That Express the CB1 Receptor
Red = abundant CB1 receptor expression Black = moderately abundant CB1 receptor expression

Adapted from Joy JE et al, eds. Marijuana and Medicine. 1999.

 CB2 Receptors

CB2

Immune System
T cells B cells Monocytes
Spleen Tonsils

Expressed primarily in immune cells

Expressed in low concentrations in CNS, but increased upon
microglial activation
Activation may reduce pain, inflammation, neurodegenerative
diseases, cocaine reward
Munro S et al. Nature. 1993;365:61-65.
Van Sickle MD et al. Science. 2005;310:329-332.
Whiteside GT et al. Curr Med Chem. 2007;14:917-936.
THC Produces Its Effects Through the Activation
of Two Types of Cannabinoid Receptors
CB1 Receptor
OH

CB2 Receptor
O

D9-THC

Therapeutic Effects
Antiemetic/antinausea
Appetite stimulant Therapeutic effects
Increased energy storage? Analgesia
Analgesia Anti-inflammatory
Side Effects -periphery
Psychomimetic effects -CNS (AD, ALS, etc)
Abuse liability Cocaine abuse?
Dependence liability No known side effects
Memory impairment
CB1 Receptor Signal Transduction Pathway

Guzman et al (2001)
Trends Pharmacol
Sci. 22:19-22.
What is the evolutionary benefit of
cannabinoid receptors?

Hey Barney,
lets hurry up and
invent fire!
 Brains Naturally Occurring Marijuana-like Chemicals
(i.e., Endogenous Cannabinoids; Endocannabinoids; eCBs)

Anandamide (Eternal Bliss) 2-arachidonoylglycerol (2-AG)

-1st isolated from porcine brain
-Activates CB1 & CB2 receptors
-Partial CB1 receptor agonist
-TRPV1 receptor agonist
-Energy regulation
-Pathological states
Devane et al. (1992) Science, 258:1946-1949
-3 orders of magnitude more abundant
than anandamide in brain
-Activates CB1 & CB2 receptors
-Full CB1 receptor agonist
-Retrograde signaling molecule
modulating synaptic plasticity
-Major precursor for free arachidonic
acid in brain
Mechoulam et al. (1995); Suigara et al. (1995) Nomura et al.
2011
Difference Between Classical
and Retrograde
Neurotransmission
 Why Arent We High on
Endocannabinoids All the Time?
 eCBs Produced and Released on Demand and
Regulated by Hydrolytic Enzymes
Phospholipids Precursors in Cellular Membranes

DAGL ABHD4 /
DAGLb PLC /
TPN22 PDEMD

2-Arachidonoylglycerol (2-AG)
Anandamide

+ O +
OH

Arachidonic Acid
 Fatty Acid Amide Hydrolase (FAAH) vs.
Monoacylglycerol Lipase (MAGL)

FAAH MAGL
-Located presynaptically -Located postsynaptically
-Major anandamide catabolic -Major 2-AG catabolic enzyme
enzyme -Major biosynthetic enzyme of
-Hydrolyzes other FAAs free arachidonic acid in brain
-PEA (anti-inflammatory) Karlsson et al. 1997; Dinh et al. 2002; Nomura et al. 2011
-OEA (anti-inflammatory)
-Oleamide (sleep-inducing)
Cravatt et al. 1996; 2001
 FAAH Metabolizes Multiple
Lipid Signaling Molecules
Anandamide: endogenous cannabinoid
O
HO
N
H

Oleamide: sleep-inducing
O
H2N

N-palmitoylethanolamine (PEA): anti-inflammatory (PPARa)

O
HO
N
H

N-oleoyl ethanolamine (OEA): anti-feeding and anti-inflammatory

substance (PPARa)
O
HO
N
H

N-acyl taurines: activate transient receptor potential (TRP) family of

calcium channels, including TRPV1 and TRPV4
Cravatt et al. 1996; 2001
Cravatt et al. 1996; 2001
 PLC DAGL

Enzymatic Regulation of 2-AG and

Lipid-Derived Eicosanoids*

MAGL

*Modified from Hsu et al. (2012) Nat Chem Biol, Supp Fig 14a
and Figure 33.1, Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e
 eCB System
2-AG
or OO OOHH
HHNN
CB11 Receptor
CB
CB Receptor
1 Receptor
OH
Anandamide
Anandamide
OH CB
CB22 Receptor
Receptor
O
D9-THC
O X
FAAH or
MAGL
D9-THC MAGL
High& Inflammation
Pain
PainHigh
& Inflammation
Cognition O
O
High
Cognition
Pain OH
Pain &
Feeding & Inflammation Pain &
InflammationPain & OH
Feeding
Cognition
Anticonvulsant
Cognition Inflammation
Inflammation Arachidonic
Anticonvulsant
Feeding
Emotionality Arachidonic acid
acid
Feeding &
& metabolites
metabolites
Emotionality
DrugAnticonvulsant
Dependence
Anticonvulsant
Drug Dependence
Emotionality
Emotionality
Drug
Drug Dependence
Dependence
 Other Putative eCBs

Noladin ether (Hanus et al. 2001)

Virodhamine (Porter et al. 2002)
N-arachidonyldopamine (NADA; Bisogno et al., 2000)
N-Oleolyldopamine (OLDA; Chu et al., 2003)
Hemopressin (Heimann et al., 2007)
CB1 Receptor Ligands
Review of eCBS
Physiological Effects of
Endocannabinoids