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Marijuana
Marijuana is a mixture of dried and crumbled leaves,
small stems, and flowering tops from cannabis sativa,
cannabis indica, cannabis ruderalis.
It can be consumed orally, as in cookies or brownies,
but is usually smoked in rolled cigarettes known as
“joints,” various kinds of pipes, or in hollowed-out
cigars called “blunts.”
The psychoactive compound Δ9-tetrahydrocannabinol
(THC), accounts for the use of cannabis as a drug and
is concentrated in plant resin (most in flowering buds).
Marijuana potency (in terms of THC content) varies
widely, depending on the genetic strain of the plant and
growing conditions.
Potency can be increased by preventing pollination and
seed production by the female plants. This marijuana is
called sinsemilla (“without seeds”). Makes up 50% of
confiscated marijuana. 11% considered “high grade”
#1 most widely used illegal drug in US; It is classified
as a mild hallucinogen
Potency also depends on:
• frequency of use
• user characteristics
• setting
• expectations
• smoking behavior
Hashish
Hashish is a cannabis derivative that
can be smoked or eaten.
It can refer to a relatively pure resin
preparation with very high
cannabinoid content, or a solvent
extract of leaves or resin.
Most potent form of marijuana
Hash oil is an alcoholic extract. A
drop is placed on a tobacco or
marijuana cigarette.
Use is fairly rare in US now
less than 1% has been confiscated
History of Marijuana
Marijuana remains a controversial
subject in our society—castigated
by many as a gateway to the socalled hard drugs, but praised by
others as an unappreciated medical
marvel.
Marijuana is produced from flowering
hemp (Cannabis sativa).
Hemp has been a major source of fiber
in many cultures for rope, cloth, and
paper.
Hemp seeds have been used for oil and
bird food.
Hemp also contains 70 unique
compounds known as
cannabinoids, plus more than 400
other identified compounds.
Early History of Marijuana
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8000 BC: first archeological record
2700-1000 BC: Medical and religious use can be traced to ancient China, India, and the
Middle East, spreading to the Arab world.
1800’s: Napoleon’s soldiers brought it to France from Egypt. It became popular with
French writers and artists. Hemp was grown and used in colonial America.
1900’s: Marijuana smoking probably came to the U.S. with Mexican and Caribbean
immigrants.
Modern History of Marijuana
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1914: Harrison Act increased taxation for grower to seller
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1926: Newspaper article links marijuana use to crime
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1930s: US Bureau of Narcotics launched a public relations campaign
to portray marijuana as a social menace that could destroy the youth of
America. The propaganda included magazine articles and antimarijuana films such as Reefer Madness.
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1936: All states regulate use, sale, and possession.
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1937: Marijuana Tax Act instituted a national registration and
taxation system aimed at discouraging all use of cannabis. Made use
illegal.
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1944: La Guardia Report downplayed serious effects
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1969: Marijuana Tax Act found to be unconstitutional
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1970’s: Marijuana use peaks; drops in 1980’s; rises again in 1990’s
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1996: First state laws legalizing Marijuana for medicinal use.
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2012: First states laws legalizing Marijuana for recreational use.
Phytocannabinoids
Marijuana has over 400 chemicals and ~ 70 phytocannabinoids
9-tetrahydro-cannabinol (THC) was identified as the major
active ingredient in 1964. Is most pharmacologically active.
Burning marijuana causes the THC to vaporize and enter the
smoker’s lungs in small particles. THC is easily absorbed
by the lungs, and blood plasma levels rise quickly.
Effective dose and latency to onset of effects are influenced by
the amount and potency of the plant used and patterns of
smoking.
Concentrations begin to decline as a result of metabolism in the
liver and accumulation in the body’s fat stores (half life:
~19 hrs; complete elimination in 2-3 weeks).
In oral use, poor absorption results in low and variable plasma
levels, probably due to degradation in the stomach and firstpass metabolism (peak effect occurs ~90 mins after
ingestion).
THC synthetics:
Dronabinol (Marinol)
Nabilone (Esamet)
Phytocannabinoids
Cannabigerol-type
CBG
Cannabielsoin-type
CBE
Cannabichromene-type
CBC
isoTetrahydrocannabinoltype
iso-THC
Cannabidiol-type
CBD
Cannabicyclol-type
CBL
Tetrahydrocannabinoland Cannabinol-type
THC, CBN
Cannabicitran-type
CBT
Endocannabinoids
• Arachidonoyl ethanolamide
(AEA), Anandamide
• 2-arachidonoylglycerol (2-AG)
• Oleamide
Endocannabinoid System Function:
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Reinforcement
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Dependence and/or Relapse
• Alcohol
• Other drugs
Endocannabinoid Physiology
Retrograde messengers:
carry information in the
opposite direction
Cannabinoid Receptors
• A cannabinoid receptor in the CNS was
identified in 1988.
• Receptors occur in many brain areas.
• Cannabinoid receptors are metabotropic
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work via G proteins to inhibit cAMP formation
Inhibits adenylate cyclase
inhibit voltage-sensitive Ca2+ channels
open K+ channels.
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CB1 receptors
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CNS (reward via mesolimbic?)
Located on axon terminals
Inhibiting many neurotransmitters
CB2 receptors
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immune system (could modulate response)
Bone
adipose (fat) cells
GI tract.
Rimonabant: CB1 antagonist
CP-55,940: CB agonist
Cannabinoid Receptors in the Brain
Cannabinoid receptors (CB1)
•cerebral cortex
•hippocampus
•basal ganglia
•cerebellum
•nucleus accumbens
Receptor Autoradiography
Brighter areas show greater
receptor density
CB1 gene (CNR1) Expression
CB1 Receptors and Mood
• Prefrontal Cortex
• Hypothalamus
• Amygdala
• Hippocampus
• Raphe nucleus
• VTA
• Locus Coeruleus
• NPH
Marijuana use as a Function of Age
Risk Factors:
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Emotional problems
Family problems
Drug use in household
Drug us by peers
Dislike of school
Poor school performance
Early age of first use
Early positive increases
dependency
If not tried by 25 then typically never use
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Negative Effects of
Marijuana
lung damage
increased heart rate
dry eyes and mouth
impaired tracking ability
memory loss
reduced locomotor activity
hypothermia
hypoalgesia
decreased sperm cell count
decreased cognitive function
decreased educational performance
rejection of mainstream ideas
anxiety or paranoia
depersonalization
derealization
agitation
altering of mood
tolerance/addiction like properties
marijuana madness
desensitization of receptors
Amotivational syndrome
Gateway drug?
Hippocampal CB1 receptors are responsible for memory
impairment
Marijuana Madness
Probability of Psychoses in Marijuana Users
Marijuana Madness
Association Model: individuals who are
already vulnerable to developing
psychosis have an increased likelihood
of using cannabis when they are young
Causal Model: heavy use predisposes
individuals to develop psychosis later in
life.
Indicator-Variable Model: one or more
other factors lead jointly to cannabis use
and psychosis proneness.
Marijuana Tolerance
Develops after high
levels or regular use
May not develop
uniformly to all effects
Animals exposed to THC
or CB1 agonists develop
tolerance
CB receptors are
desensitized and
downregulated following
chronic THC exposure
Marijuana
Dependence
Dependence:
• Difficulty in stopping use
• Craving the drug
• Unpleasant withdrawal symptoms
Most users do NOT become dependent
Rehabilitation:
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Similar to other drug treatments
Cognitive behavioral therapy
Motivation enhancement therapy
Patients are vulnerable to relapse
Marijuana Withdrawal
Withdrawal:
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No DSM-V listing
Not life threatening but
unpleasant
Some research supports notion
Begins 1 day after last dose
Lasts 4 – 12 days
Symptoms:
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Increased irritability
Increased Anxiety
Decrease mood
Increased sleep problems
Increased aggressiveness
Decreased appetite
Positive Effects of Marijuana
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reduced nausea
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reduced pain
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reduced MS spasticity
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reduced symptoms of GI tract disorders
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reduced cancer formation
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reduced symptoms of neurodegenerative
disorders
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reduced symptoms of psychiatric
disorders
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CB1 antagonists can reduce obesity
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Increased fear alleviation
History of Medicinal Marijuana
1937: after Marijuana Tax Act medicinal use of marijuana dropped so
other medicines were developed
1970’s to present: increased interest in medicinal use for:
Glaucoma
Chemo-based Nausea (antiemetic)
1985: Synthetic THC, Marinol (Dronabinol) approved as antiemetic
1993: Marinol approved as appetite stimulant for AIDS patients
1999: Institute of Medicine – recommends medicinal use
2014: 23 states and DC allow medicinal use
The New
Medicinal
Marijuana
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Nabiximols
• THC
• CBD
*FDA approved
Cannabis and Multiple Sclerosis
Cannabidiol (CBD)
•Pain
•Shaking
•Spasms
•Spasticity
•Fatigue
•Sleep Quality
•Mobility
•Well Being
Cannabis and Cancer
MMP-2: enzyme that promotes spread of cancer
Obesity Control
CB1 antagonist: AM6545
• Acts peripherally
• Reduces food consumption in
humans and non-human animals
• May be useful in treating obesity