Background and History of Marijuana
• Produced from the flowering
hemp (Cannabis Sativa).
• Hemp was historically
important as a major source of
fiber for rope making
– Shipping
• Contains more than 60 unique
compounds collectively known
as cannabinoids
• Some of these compounds are
psychoactive
– Δ9 – tetrahydrocannabinol
(THC)
Background and History
• Cannabis can be obtained in a number of forms
– Marijuana – mixture of dried leaves, small stems, and
flowering tops of Cannabis plants
• Usually smoked
• Can be consumed (often in baked goods – cookies or
brownies).
• Potency varies depending on
– genetic strain
– growing conditions
» If you prevent pollination (which prevents seed production
in female plants) you can achieve higher potency
» Known as sinsemilla (without seeds)
Background and History
• Hashish
– Collected and pressed plant resin
– Can be smoked or eaten
– Potency depends on how collected, but it is generally
more potent than marijuana
• Hash oil
– An even more potent extract of the marijuana plant
resin
– Sometimes a drop is placed on a typical cigarette and
smoked.
– Or a drop can be added to a marijuana cigarette to
increase its dose.
13.3 The potent form of cannabis called hashish
Hash Oil
Background and History
• Cannabis is thought to have originated in central
Asia (probably China).
• There is evidence of hemp rope dating back to
8,000 B.C.
• Western interest did not begin until the early to
mid nineteenth century.
• Napoleon’s soldiers thought to have brought
hashish back to France from Egypt
• French physician Jacques-Joseph Moreau also
brought hashish back to Paris after traveling to
the Middle East.
– “club of hashish eaters”
• Writers and artists
Background and History in US
• Dates back to colonial era
• George Washington was a hemp farmer
– Unlikely aware of psychoactive effects
– Grown for fiber
• Practice of smoking marijuana likely brought into
the US in the early 1900s
– Mexican/American border
• Mexican immigrants
– New Orleans and other ports on the Gulf of Mexico
• Caribbean sailors
• West Indian immigrants
Background and History in US
• Marijuana use spread rapidly in the US
• Marijuana tax act in 1937
• Overturned by Supreme Court in 1969
• Controlled substances Act of 1970
– Schedule 1 drug.
Basic Pharmacology of Marijuana
• Israeli researchers: Gaoni and Mechoulam
(1964) identified THC as the major active
ingredient of Cannabis Sativa.
Basic Pharmacology of Marijuana
• A typical joint consists of around 0.5 grams to 1 gram of
cannabis.
– THC content can be around 4% or higher
– If about 4% then a 1 gram joint contains about 40 mg of THC
• Burning causes the THC to vaporize and enter the
smokers lungs in small particles
– Only about 20% of the original THC content gets absorbed
• There can be substantial variation in the amount of THC
absorbed based on
– The potency of the marijuana
– The amount smoked
– The pattern of smoking
Basic Pharmacology of Marijuana
• Experienced marijuana users regulate the
volume and frequency of “puff” to control the
behavioral effects of the drug.
– Interestingly controlled experimental studies have
failed to show a substantial effect of breath holding
– Though Block et al. (1998) found that there was a
modest subjective effect of breath holding for 15
seconds rather than 7 seconds.
• So there may be something to the practice of holding the
smoke in.
Basic Pharmacology of Marijuana
• THC is absorbed
through the lungs
• Causes rapidly rising
levels of THC in blood
plasma
• After peak levels are
reached, Plasma THC
levels begin to decline
– Metabolism by liver
– Accumulation of the
drug in fat stores
Basic Pharmacology of Marijuana
• Oral consumption of marijuana
– Leads to prolonged but poor absorption of THC
• Results in low and variable plasma concentrations
• Probably due to degradation in stomach, and first pass metabolism
by the liver.
• THC is converted into several metabolites
– 11-hydroxy-THC
– 11-nor-carboxy-THC (THC-COOH)
• These metabolites are excreted in feces and urine
– Blood levels of marijuana decline quickly
– But elimination from the body is much slower.
• The drug persists in fatty tissue
• Sensitive urine screening tests can detect THC-COOH more than 2
weeks following last use.
Mechanism of Action
•
•
It wasn’t until 1988 that the receptors
for cannabanioids were discovered
Subsequently, it was discovered that
cannabinoid receptors were expressed
in many brain regions, including the:
–
–
–
–
Basal ganglia
Cerebellum
Hippocampus
Cerebral cortex
•
–
Also limbic system
•
•
–
•
Especially frontal cortex
Hypothalamus
Anterior cingulate cortex
Absence of receptors in brain stem
may explain low toxicity (hard to
overdose).
Key for image
–
–
CB1 receptor densities
Yellow>Red>Blue
• Not surprisingly the location of cannabinoid
receptors correspond with the behavioral effects
of cannabinoids
– Locomotor activity
– Coordination
– Memory
• There are 2 forms of the cannabinoid receptors
– CB1 in the CNS
– CB2 in the periphery (seems to be involved in immune
system).
CB1 receptors
• Metabotropic
– Inhibition of cAMP
– Inhibition of voltage sensitive CA++ channels
– Activation of K+ channels
• Excitation or Inhibition?
• Typically the receptors exist on the axon terminal rather
than on the postsynaptic cell.
– Affects many neurotransmitter systems
•
•
•
•
•
•
Acetylcholine
Dopamine
Norepinephrine
Serotonin
Glutamate
GABA
Agonists and Antagonists
• THC is of course the classic cannabinoid
receptor agonist
• First useful antagonist was developed in
1994
– SR 141716 (rimonabant)
– Selective antagonist for CB1 receptors
– Orally active (thus, easy to administer to
humans)
• We will discuss the effects of this drug later
Endocannababinoids
• The existence of cannabinoid receptors led
researchers to search for an endogenous
neurotransmitter
– Israeli scientists: Devane et al. (1992)
– Arachidonoyl ethanolamide
• Anandamide
• From Sanskrit - ananda “bringer of inner bliss and tranquility”
• Other endogenous substances have now been
found
– Collectively referred to as the endocannabinoids
• The endocannabanoids are generated from
arachidonic acid
– A fatty acid found in the cell membrane
• Unlike classic neurotransmitters they are very
lipid soluble
– Can’t be stored in vesicles
• Would pass right through the membrane
• Believed they are made and released as needed
– One mechanism appears to be a rise in intracellular
Ca++ levels.
• Enzymes involved in generation of endocannabinoids are
Ca++ sensitive
• After release endocannabinoids are taken up
from the extracellular fluid by specific
transporters
– Seems to inactivate endocannabinoids
• Inhibition of this transporter (AM 404) enhanced the effects
anandamide in animals
– Once in the cell endocannabinoids are metabolized
be enzymes
• Fatty acid amide hydrolase (FAAH)
• Genetic knock out mice that lack FAAH show elevated
anandamide levels in the brain
• Endocannabinoids appear to work by
modulating the effects of other neurotransmitter
systems
• Either by suppressing inhibition of interneurons
– Depolarization induced suppression of inhibition (DSI)
• Suppress activity of GABA releasing neurons
• Or by suppressing excitation of interneurons
– Depolarization induced suppression of excitation
(DSE)
• Suppress activity of Glutamate releasing neurons.
Depolarization-induced Suppression of Inhibition - DSI
• Depolarization-induced suppression of inhibition (DSI)
– Known to occur for some time.
– A form of fast acting retrograde signaling
• Remember nitric oxide?
– Prominent effect in the hippocampus and cerebellum
• Endocannabinoids appear to be retrograde messengers
– The are synthesized and released in response to depolarization
of the post synaptic cell
• Influx of Ca++ through voltage gated channels
– Following release they cross the synaptic cleft and activate CB1
receptors
• They then inhibit neurotransmitter release from the presynaptic
terminal
• In the hippocampus (an example)
– Endocannibinoids are generated by pyramidal
neurons (principle output neurons of the
hippocampus)
• Diffuse to nearby GABAergic interneurons and inhibit them
• Inhibition of GABA release allows the pyramidal cells to fire
more rapidly
– Inhibition of inhibition = excitation
• Similar mechanisms likely occur in other brain
regions and other neurotransmitter systems
13.9 Retrograde signaling by endocannabinoids reduces GABAergic inhibition
Evidence that endocannabinoids play a role in DSI
• Ohno-Shosaku et al. (2001)
– Cultured hippocampal neurons
– Found that depolarization of the postsynaptic
neurons lead to suppression of inhibition in
about 2/3 of neuron pairs
• Due to inhibition of GABA
– Those neurons that displayed DSI responded
to the CB1 synthetic agonist (WIN55, 2122)
• Mimicked DSI
– Rimonabant blocked this effect
Evidence that endocannabinoids play a role in DSI
• Varma et al. (2001)
– DSI was completely absent in hippocampal slices
prepared from CB1 receptor knockout mice
• There is also a phenomenon known as
depolarization-induced suppression of excitation
(DSE).
– This involves suppression of typical excitation
produced by glutamate
– Cannabinoids appear to play a role here as well.
Iversen 2003
• These findings suggest that endocannabinoids are
involved in the rapid modulation of synaptic transmission
in the CNS via a retrograde signaling system.
– Causing inhibitory effects on both excitatory and inhibitory
neurotransmitter release that persists for tens of seconds
• When we take cannabinoids they cause long-lasting
activation of CB1 receptors in all brain regions
– Rather than short localized effects
• This will temporarily override any modulatory effects that
cannabinoids normally cause
Acute Behavioral Effects
• Iversen (2000) separates the subjective effects
of moderate doses of marijuana into four stages
– 1) The “buzz”
• A brief period of initial responding
– Lightheaded
– Perhaps slightly dizzy
– Tingling sensation in extremities is fairly common
– 2) The “high”
• Feelings of euphoria and exhilaration
• Sense of disinhibition
• Often manifested as increased laughter.
3) “stoned”
• Calm, relaxed, dreamlike state
• Sometimes people report
–
–
–
–
–
Floating sensation
Enhanced visual and auditory perception
Visual illusions
Tremendous slowing of time passage
Some feel increased sociability; others feel a desire to be
alone
4) “comedown”
• Often preceded by hunger, or empty feeling in stomach
“munchies”
• People report feeling tired, listless, weak.
– Everyone initially very talkative, but as they comedown
conversations slows and people become sleepy
• Usually leads to sleep sometimes with colorful dreams
• Marijuana can cause strong feelings of anxiety,
panic, or paranoia.
– More likely to be reported by first time users, or the
result of taking large doses of the drug
Acute Physiological effects
• Increased blood flow to the skin
– Sensation of warmth or flushing
• Increased heart rate
– Pounding pulse
• Increase in hunger
– Munchies
• Recognized as a therapeutic effect of marijuana
• Expectations about the drug can influence the
effects of the marijuana
– Kirk et al. (1998)
• Some given THC capsules
• Some given placebo
• Some informed
• Some uninformed
– Informed group gave higher ratings for liking the drug
and wanting more drug
• This was also true for the group that received placebo, but
were told they received THC
• The subjective effects of
marijuana are at least partially
mediated by CB1 receptors.
– Self reports of feeling high or
stoned were significantly
inhibited by the antagonist SR
141716
• Notice the same sort of effects
occurred for heart rate (a less
subjective measure).
• Unknown if there is more than
one mechanism of marijuana
effects, or if they didn’t use a
high enough dose of
antagonist to fully block the
effects.
Therapeutic uses of cannabinoids
• Antiemetic effects
– There are presently synthetic forms of THC that are
prescribed to treat the nausea and emesis (vomiting)
associated with chemotherapy
• Dronabinol
• Nabilone
– Animal Studies have shown that this effect appears to
be CB1 dependent.
– In fact in one susceptible species (the shrew) the
CB1 antagonist rimonabant is emetic.
• This effect can be blocked by THC or WIN55,2122
Appetite stimulant
• Dronabinol is also approved for use as an appetite
stimulant in AIDS patients suffering from anorexiacachexia (wasting syndrome).
– THC also stimulates food intake in experimental animals
• For high-fat or sweet high-fat diets
• Not for lab chow
• This effect is blocked by rimonabant
– Rimonabant given on its own suppresses food intake
• Led to reduced body weight in adult non-obese rats.
• Implicates CB1 receptors
• Perhaps a treatment for obesity?
• These effects may work through the appetite
suppressing hormone leptin.
– hypothalamus
Cannabinoids and pain
• Cannabis was widely used in the 19th
century for pain relief
• Cannabinoid receptors exist at various
levels in the pain pathway
– Peripheral nerve endings in the spinal cord
– Anterior cingulate cortex
Animal studies
• Animal studies show that THC and
synthetic cannabinoids have antinociceptive effects.
– Have to rule out motor effects
• Cannabinoids decrease activity
– Typically measure how quickly an animal will avoid pain
» Hot plate
» Tail flick
– Could be same pain but less movement
Cannabinoids, pain relief, animal studies
• Shown that cannabinoids suppress electrophysiological
responses of spinal cord neurons to pain
• Shown that cannabinoids work when injected directly
into spinal cord, brain stem, or spinal cord
– Localized effects that should be less likely to affect activity levels
• The anti-nociceptive effects of cannabinoids are blocked
by rimonabant
– Showing that CB1 receptors are directly involved
• Pain increases release of anandamide in the
periaquaductal grey
Cannabinoids and pain relief
• There is evidence that there may be an
interaction between the cannabinoid and
the opioid system in the relief of pain
– The systems seem to potentiate each other
– This potentiation can be blocked by
rimonabant or naloxone
• Indicating that both CB1 and opiate receptors are
involved
• There is also evidence that cannabinoids may have some benefit for
–
–
–
–
Glaucoma (pressure in the eye)
Multiple sclerosis
Spinal cord injury
Traumatic brain injury
• Development of cannabinoid clinical applications has been slow
• Why?
– Lack of large scale controlled clinical studies
• Federal government tends to discourage efforts to develop and license new
cannibinoid medicatons
– Concerns about psychoactivity
• cannabinoids are psychoactive even if taken orally
– This leads some physicians to be concerned about abuse
– Route of administration
• Works best if smoked
• Daily smoking can cause respiratory issues
• Nevertheless, some states have legalized smoking marijuana
Marijuana use can lead to deficits in cognition
• Clinical accounts of marijuana intoxication have
noted deficits in thought processes and verbal
behavior
– Illogical disordered thinking
– Fragmented speech
– Difficulty remaining focused on a given topic of
conversation
• Experimental assessment
– There are decrements on a variety of tasks
• Verbal
– Recall and recognition of word lists
Cognitive deficits
• Spatial working memory: Ilan et al. (2003)
A dot stimulus was displayed in one of six positions on each trial.
Subjects had to decide whether the spatial location of the
dot on each trial matched the location of the dot two trials before.
Because which dot occurred two trials before changes with each
passing trial, this task requires frequent manipulation of to-be-remembered items.
Cognitive deficits
• Time estimation
– Lieving et al. (2006)
• Asked to push one button for a short sample (2-s)
and a different button after a long sample (4-s)
– train until performing well
• Test with a variety of samples between 2- and 4-s
• Those on marjiuana were more likely to judge time
samples as long.
– Indicating that time had sped up for the individual making short intervals seem long
Cognitive deficits
• Explicit memory
– Oral Dronabinol (Marinol)
– Subjects listened to a short written passage
• Similar to a news bulletin on the radio
• Tested before and after drug or placebo
administration
– 1 hour before = 0 point on next graph
– They were then tested again 2 and 6 hours
after treatment
Cognitive deficits
• Low dose of THC did
not affect memory
• High dose clearly did
• Memory for the
content of a story
compares nicely with
real world task of
following a
conversation.
Cognitive deficits
• Clearly there are many cognitive effects of
marijuana intoxication
• There is evidence that prior usage of
marijuana can reduce these adverse
cognitive effects
– Behavioral “cognitive” tolerance?
• Learn to focus / pay more attention?
Psychomotor performance
• Low doses of marijuana do not affect
psychomotor performance much
• Higher doses do, even for regular users
– Particularly for demanding tasks
• Like driving.
Animal studies
• Early studies show that THC can cause
motor impairments, cataplexy (lack of
voluntary movement), hypothermia, and
analgesia.
• Most of the behavioral effects of THC are
abolished in CB1 receptor knockout mice.
– Indicating these effects are mediated by CB1
receptors
Effects on animal learning and memory
• Cannabinoids disrupt performance on several
learning tasks
– Radial arm maze
– Morris water maze
– Delayed non-match-to-position task.
• Left or right bar
– Insert one
– When rat responds the bar is retracted
• Impose delay
• Insert both bars
– Must choose the 1 that was not presented initially
• Considered a test of short term memory
Effects on animal learning and memory
• Cannabinoids can impair radial arm maze
performance when injected directly into
hippocampus
• It has also been shown that activation of CB1
receptors in the hippocampus decreases
hippocampal synaptic transmission and
interferes with long-term potentiation
• Perhaps the effects in humans are also due to
impaired hippocampal functioning
Effects on animal learning and memory
• There is evidence that CB1
receptors may be involved in
extinction or reversal learning
• Varvel and Lichtman (2002) found
the CB1 knockout mice show
impaired reversal learning in the
Morris Water Maze
– Perseverate?
– Damage to which brain area tends
to cause perseveration?
– There is also evidence that
humans exposed to marijuana
have a decreased ability to inhibit
responding
Cannabinoids are reinforcing to both humans and other animals
• Chait and Zacny (1992) found that regular
marijuana users could discriminate
marijuana from placebo cigarettes
– All preferred marijuana if given a choice
– Same effects occurred with pure THC taken
orally compared to placebo
• Also shown that marijuana users preferred
1.95% THC content to 0.63% THC
Marijuana and reward in animals
• It was initially thought that
animals did not find marijuana
rewarding.
– Perhaps early studies used
too high of doses leading to
aversive reactions
• Squirrel monkeys have been
shown to self-adminster THC
– These studies used lower
doses within the range of a
single drag of marijuana
• Lever pressing was blocked
with pretreatment with SR
141716
– Indicating that the
reinforcement depended on
CB1 receptors
Marijuana and reward in animals
• Rats and mice
– Will self administer low doses of WIN 55,2122 (synthetic CB1 receptor agonist).
• Mice also show CPP to THC injection
• Only for the low dose
• Only if preexposed to THC in their home cage
– Indicates that first exposure to THC may be
somewhat aversive regardless of dose
– Also indicates that the animals found high
doses to be aversive
Mechanisms of cannabinoid reinforcement
• One factor may be activation of the
mesolimbic DA system.
– Cannabinoids have been shown to stimulate
firing of DA neurons in the VTA
– Also to enhance DA release in NA
Mechanisms of cannabinoid reinforcement
• There is evidence that the close interaction of
the cannabinoid and opioid systems may play a
role in reward
– For both cannabinoids and opiates
• Systemic Naltrexone reduced THC self-administration in
squirrel monkeys
• CPP to low doses of THC did not occur in μ-opioid receptor
knock out mice
• CPA to high doses of THC did not occur in к-opioid receptor
knock out mice
• Microinfusion of μ-opioid antagonist naloxonazine into the
VTA of rats blocked DA release in NA
– by heroin
– also by THC.
• Recently knockout and SR 141716 studies have
provided evidence that the endocannabinoid
system may play a role in the process of
reinforcement, dependence, and relapse of a
number of drugs including
–
–
–
–
Ethanol
Opioids
Cocaine
Nicotine
• Perhaps future treatments for drug addiction
may involve the endocannabinoid system
Cannabis use
• Cannabis is one of the most widely used
intoxicants
• Almost half of all 18 year olds in the USA and in
most European countries admit to having tried it
at least once
– About 10% of that age group are regular users
• The number of new marijuana users per year
has remained fairly steady (1995-2001).
– Suggests government efforts to dissuade use has not
been very effective.
Cannabis use
• Initial use of
marijuana use
typically occurs in
adolescence
• Peak age for trying
marijuana is 17
• People who have not
tried the drug by mid
twenties are unlikely
to begin use
Marijuana tolerance
• Human literature is variable
– Some studies have shown tolerance
– But many have shown that the high produced by a
given dose of THC is similar for heavy or light users
• Animal literature is more consistent
– Animals exposed repeatedly to THC develop a
profound tolerance
– Appears to be pharmacodynamic tolerance
• Rats given daily THC injections over a 3-week period
– Showed gradual reductions in CB1 receptor densities
– Also reduced responsivity of receptors to cannabinoid agonists
» Measured by G-protein activation = reduced as exposure
increased
13.16 Desensitization of cannabinoid receptors produced by chronic THC exposure
Marijuana Dependence
• For many years cannabis was not considered a drug of addiction
• Withdrawal did not lead to any obvious physical symptoms in people
or animals
• These attitudes have changed recently
• The DSM IV definitions of substance dependence and substance
abuse may have played a role
– Certainly high proportions of regular cannabis users would meet these
definitions
– Swift et al (2001)
• 10641 Australians 18 or older
• Estimate 1/3 of regular cannabis users fell within the definition of substance
abuse (11%) or substance dependence (21%)
– US survey (Anthony et al., 1994)
• 46% admitted trying
• estimate that 9% of those users became dependent
Marijuana Dependence
• There is some evidence for a mild withdrawal syndrome
as well
– Symptoms include:
•
•
•
•
•
•
Craving for cannabis
Decreased appetite
Sleep difficulty
Strange dreams
Weight loss
Sometimes emotional issues
– Anger
– Aggression
– Irritability
• These symptoms are similar to that seen with nicotine
• Symptoms are greatest during first 1 or 2 weeks of
withdrawal.
13.17 Time course of overall withdrawal discomfort in heavy marijuana users
Effects of Chronic Cannabis use
• There is a negative correlation between
cannabis use and educational performance in
young people
–
–
–
–
Poorer grades
Negative attitude about school
Increased absenteeism
Increased drop-out rates
• Amotivational syndrome?
• Correlation and causation
• Health effects
– No overdose
– Lung damage?
• Don’t smoke as much as cigarettes
• But - higher concentration of tar and other
carcinogens
• Thus heavy smoking is linked to
– Increased risk for bronchitis
– Cellular abnormalities in lungs
» Some considered precancerous
• Clear link to lung cancer not determined
– Immune system
• THC can suppress the immune system
• Impairs resistance to bacterial and viral infections
– Mostly in-vitro studies
– Difficult to know if it has real life effects
– Reproductive function?
• Can suppress luteinizing hormone (LH) in women
– Not present in regular users (Tolerance)
• Can decrease sperm count
– Only under very heavy conditions (10 joints per day for 4
weeks)
– Went away after a few weeks of abstinence
• No convincing evidence that reproductive problems stem
from marijuana use