14
Marijuana and the
Cannabinoids
14 Marijuana and the Cannabinoids
Background and History of Marijuana
Basic Pharmacology of Marijuana
Mechanisms of Action
Acute Behavioral and Physiological
Effects of Cannabinoids
Cannabis Abuse and the Effects of
Chronic Cannabis Exposure
Background and History of Marijuana
In the 1930s, the 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 anti-marijuana films such
as Reefer Madness.
Figure 14.1 Poster advertising the 1936 film Reefer Madness
Background and History of Marijuana
Marijuana remains a controversial
subject in our society—castigated by
many as a gateway to the so-called
hard drugs, but praised by others as an
unappreciated medical marvel.
Background and History of Marijuana
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.
Figure 14.2 Cannabis plants
Background and History of Marijuana
Hemp also contains 70 unique
compounds known as cannabinoids,
plus more than 400 other identified
compounds.
The psychoactive compound Δ9tetrahydrocannabinol (THC),
accounts for the use of cannabis as a
drug.
Background and History of Marijuana
Marijuana is a mixture of dried and
crumbled leaves, small stems, and
flowering tops.
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 hollowedout cigars called “blunts.”
Background and History of Marijuana
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”).
Background and History of Marijuana
Hashish is a cannabis derivitive 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.
Hash oil is an alcoholic extract. A drop is
placed on a tobacco or marijuana
cigarette.
Figure 14.3 The potent form of cannabis called hashish
Background and History of Marijuana
Cannabis probably originated in China.
Medical and religious use can be traced
to ancient China, India, and the Middle
East, spreading to the Arab world.
Napoleon’s soldiers brought it to France
from Egypt. It became popular with
French writers and artists.
Figure 14.4 An 8000-year time line of cannabis use around the world
Background and History of Marijuana
Hemp was grown in colonial America,
but marijuana smoking probably came
to the U.S. with Mexican and Caribbean
immigrants in the early 1900s.
In 1937, the Marijuana Tax Act instituted
a national registration and taxation
system aimed at discouraging all use of
cannabis. It was overturned in 1969, but
cannabis is still tightly controlled.
Background and History of Marijuana
THC was identified as the major active
ingredient in 1964.
Burning marijuana causes the THC to
vaporize and enter the smoker’s lungs
in small particles.
Effective dose and latency to onset of
effects are influenced by the amount
and potency of the plant used, and
patterns of smoking (e.g., breathhold
duration).
Figure 14.5 Chemical structure of 9-tetrahydro-cannabinol (THC)
Background and History of Marijuana
THC is easily absorbed by the lungs, and
blood plasma levels rise quickly.
Concentrations begin to decline as a
result of metabolism in the liver and
accumulation in the body’s fat stores.
In oral use, poor absorption results in low
and variable plasma levels, probably
due to degradation in the stomach and
first-pass metabolism.
Figure 14.6 Mean time course of plasma THC concentrations
Background and History of Marijuana
Blood THC levels decline rapidly after
smoking marijuana, but complete
elimination from the body is much
slower because of persistence in fat
tissues.
The gradual movement of THC
metabolites back out of fat stores
means that urine screening tests can
detect them more than 2 weeks after a
single marijuana use.
Mechanisms of Action
A cannabinoid receptor in the CNS was
identified in 1988.
Receptors occur in many brain areas.
CB1 is the receptor found in the CNS.
CB2 occurs in the immune system and
other tissues such as bone, adipose
(fat) cells, and the GI tract.
Figure 14.7 Autoradiogram of a horizontal section through a rat brain
Mechanisms of Action
Cannabinoid receptors are metabotropic;
they work via G proteins to inhibit cAMP
formation, inhibit voltage-sensitive Ca2+
channels, and open K+ channels.
CB1 receptors are located on axon
terminals. By activating these
presynaptic receptors, cannabinoids
can inhibit the release of many
neurotransmitters.
Mechanisms of Action
Synthetic cannabinoid agonists and
antagonists have been developed for
research and potential therapeutic use.
THC given to mice induces reduced
locomotor activity, hypothermia,
catelepsy, and hypoalgesia—mediated
through CB1 receptors.
CB1 receptors also play an important role
in the reward system.
Mechanisms of Action
Cannabinoids adversely affect cognitive
function, which has been studied in
animal models.
Microinjection of THC or the synthetic
cannabinoid agonist CP-55,940 into the
hippocampus produced memory deficits
in the radial arm maze.
The effects can be completely blocked
by the antagonist rimonabant.
Figure 14.8 Hippocampal CB1 receptors are responsible for memory impairment
Mechanisms of Action
Other studies have shown that
cannabinoids inhibit the induction of
long-term potentiation (LTP) in the
hippocampal CA1 area.
Mechanisms of Action
Why do human brains have receptors for
a compound made by plants?
There must be an endogenous
neurotransmitter-like substance that
acts on the receptors.
Several of these have now been
discovered—the endocannabinoids.
Mechanisms of Action
Two main endocannabinoids have been
found: arachidonoyl ethanolamide
(AEA), or anandamide, and 2arachidonoylglycerol (2-AG).
They are retrograde messengers—
carry information in the opposite
direction from normal (i.e., postsynaptic
to presynaptic).
Figure 14.9 Chemical structures of the endocannabinoids anandamide and 2-arachidonoylglycerol
(2-AG)
Mechanisms of Action
They are synthesized and released in
response to depolarization of the
postsynaptic cell due to the influx of
Ca2+.
The endocannabinoids then cross the
synaptic cleft, activate CB1 receptors on
the nerve terminal, and inhibit Ca2+mediated neurotransmitter release from
the terminal.
Figure 14.10 Retrograde signaling by endocannabinoids
Mechanisms of Action
To determine the roles of anandamide
and 2-AG, researchers use the the CB1
receptor antagonist rimonabant, and
CB1 and CB2 knockout mice.
Pain perception: both approaches
produce mice with hyperalgesia
(increased pain sensitivity).
Cannabinoid drugs have been used to
treat pain and other medical conditions.
Mechanisms of Action
Dronabinol (Marinol), a synthetic form of
THC and the THC analog nabilone
(Cesamet) are used to treat nausea and
emesis in cancer chemotherapy
patients.
Nabiximols (Sativex) is a cannabis
extract used to treat pain and spasticity
in multiple sclerosis patients (not yet
approved in the U.S.).
Mechanisms of Action
The anatomy and functioning of the
endocannabinoid system is becoming
well known.
A great deal of research is ongoing to
develop cannabinoid medications to
treat a variety of conditions, including
GI disorders, pain, cancer,
neurodegenerative diseases and
psychiatric disorders.
Box 14.1, Figure A CB1 receptors are widely expressed in the neural circuitry of the human brain
that regulates mood
Mechanisms of Action
Medical marijuana—smoked marijuana
as a medication.
Many states now permit legal use, but
clinical studies of its efficacy have
shown mixed results.
Smoked marijuana has the potential for
adverse health effects and abuse; most
researchers favor development of
cannabinoid-based drugs instead.
Mechanisms of Action
Endocannabinoids enhance the incentive
motivational properties of food and
food-mediated reward.
CB1 receptor antagonists reduce food
consumption in animals and human
subjects.
AM6545, a peripherally-acting CB1
antagonist may be useful in treating
obesity.
Figure 14.11 Food intake and body weight gain are reduced in rats
Mechanisms of Action
Learning and memory: some studies
suggest endocannabinoids play a
greater role in extinction of learned
responses than in response acquisition.
This has been demonstrated with
auditory fear conditioning of rats and
mice. CB1 knockout mice do not show
normal extinction of the freezing
response.
Figure 14.12 Role of the endocannabinoid system in extinction of auditory fear conditioning (Part 1)
Figure 14.12 Role of the endocannabinoid system in extinction of auditory fear conditioning (Part 2)
Mechanisms of Action
In humans, a single nucleotide
polymorphism in the FAAH gene has
been discovered that results in
increased endogenous anandamide
levels.
People homozygous for the allele did not
habituate to images of threatening
faces.
The endocannabinoid system may be
involved in the alleviation of fear.
Acute Behavioral and Physiological Effects of Cannabinoids
Effects of cannabinoid use vary
depending on dose, frequency of use,
characteristics of the user, and the
setting in which use occurs.
Subjective and behavioral effects of
marijuana use can be separated into
four stages: the “buzz,” the “high,” the
stage of being “stoned,” and the “comedown.”
Acute Behavioral and Physiological Effects of Cannabinoids
The “high” is associated with feelings of
euphoria and exhilaration, and a sense
of disinhibition.
Relaxation is the most commonly
reported effect of being “stoned.”
Acute Behavioral and Physiological Effects of Cannabinoids
Physical responses include increased
blood flow to the skin and flushing,
increased heart rate, and increased
hunger.
Effects of marijuana are at least partially
mediated by CB1 receptors—effects are
significantly reduced by pretreatment
with rimonabant.
Figure 14.13 Reduction in the subjective and physiological effects of smoked marijuana
Acute Behavioral and Physiological Effects of Cannabinoids
Smoking marijuana can sometimes
produce transient psychotic symptoms
such as depersonalization,
derealization, agitation, and paranoia.
Expectation also plays a role in what
effects the drug will produce, as shown
by placebo studies.
Acute Behavioral and Physiological Effects of Cannabinoids
Plasma THC levels peak much more
rapidly after IV injection or marijuana
smoking than after oral ingestion.
In smokers, maximum intoxication occurs
some time after the cigarette has been
finished, when plasma THC is already
declining—brain and plasma THC
concentrations are not yet equilibrated
when the plasma level peaks.
Figure 14.14 Time course of plasma THC concentrations (Part 1)
Figure 14.14 Time course of plasma THC concentrations (Part 2)
Acute Behavioral and Physiological Effects of Cannabinoids
Marijuana affects cognitive functions and
psychomotor performance.
Decreased performance for a variety of
verbal, spatial, time estimation, and
reaction time tasks has been noted.
Cannabinoids appear to interfere with all
aspects of memory processing.
Acute Behavioral and Physiological Effects of Cannabinoids
One study showed dose-dependent
deficits in verbal memory tasks at 2 and
6 hours following oral THC
administration to infrequent cannabis
users.
Figure 14.15 Oral THC produces a dose-dependent impairment in explicit memory
Acute Behavioral and Physiological Effects of Cannabinoids
Heavy cannabis use over a long period
may lead to impaired executive
functioning for at least 2 to 3 weeks
following cessation of use.
Some data suggest that heavy, long-time
users may continue to show impairment
in decision-making, planning, and
concept formation.
Acute Behavioral and Physiological Effects of Cannabinoids
Marijuana can affect psychomotor
functioning under demanding task
conditions, such as driving.
Use of cannabis with or without alcohol is
a risk factor in automobile accidents.
Acute Behavioral and Physiological Effects of Cannabinoids
Cannabinoids are reinforcing:
In one study, regular marijuana users
could discriminate THC-containing
marijuana cigarettes from placebos with
no THC, and all subjects preferred the
marijuana with THC when given a
choice.
Acute Behavioral and Physiological Effects of Cannabinoids
Animal studies have also demonstrated
reinforcing properties.
Lever pressing by squirrel monkeys for
THC stopped when placebos were used.
Lever pressing for THC was completely
blocked by pretreatment with
rimonabant, indicating that the
reinforcing effect was dependent on CB1
receptor activation.
Figure 14.16 Acquisition of THC self-administration by squirrel monkeys
Acute Behavioral and Physiological Effects of Cannabinoids
Mechanisms for reinforcement:
Activation of the mesolimbic dopamine
(DA) system.
Interactions between the cannabinoid
and opioid systems may play a role in
cannabinoid reward and reinforcement;
opioid agonists enhance cannabinoid
self-administration, and opioid
antagonists have the opposite effect.
Acute Behavioral and Physiological Effects of Cannabinoids
The endocannabinoid system may play a
role in reinforcement, dependence,
and/or relapse for a number of other
drugs, including ethanol.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Marijuana use typically begins in
adolescence and peaks during young
adulthood.
If an individual has not yet tried
marijuana by his or her mid-twenties, he
or she is unlikely to begin at a later age.
Figure 14.17 Probability of initiating marijuana use as a function of age
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Many adolescent users have already had
experience with alcohol and/or
cigarettes, leading to the hypothesis
that alcohol and tobacco are “gateway”
drugs to marijuana use, which in turn
may serve as a gateway to other illicit
drugs.
These hypotheses are very difficult to
substantiate.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Risk factors in development of heavy
marijuana use by adolescents include
emotional problems in the family, heavy
drug use in the household and/or by
peers, dislike of school and poor school
performance, and an early age of first
use of marijuana.
Users that have more positive responses
to early use have greater risk of
becoming dependent.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Looking at usage from adolescence to
age 37, investigators identified five
patterns:
1. Non-users or experimenters
2. Occasional users
3. Quitters or decreasers
4. Chronic users
5. Increasing users
Figure 14.18 Trajectories of marijuana use from the adolescent period to approximately age 37
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Tolerance and Dependence
Animals exposed to THC or other CB1
agonists develop tolerance to the
behavioral and physiological effects of
these compounds.
It appears to involve a combination of
desensitization and down-regulation of
CB1 receptors.
Figure 14.19 Desensitization of cannabinoid receptors produced by chronic THC exposure
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Risk of dependence is related to drug
use patterns. People who progress to
daily use have a 50% probability of
become dependent.
Dependence is manifested as a difficulty
in stopping one’s use, a craving for
marijuana, and unpleasant withdrawal
symptoms.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Withdrawal symptoms include irritability,
increased anxiety, depressed mood,
sleep disturbances, heightened
aggressiveness, and decreased
appetite.
These are similar to the symptoms of
nicotine withdrawal.
Figure 14.20 Time course of overall withdrawal discomfort in heavy marijuana users undergoing
abstinence
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Development of the CB1 receptor
antagonist rimonabant allowed
researchers to test for dependence and
withdrawal in animal models.
Precipitated withdrawal—rimonabant
blocks the receptors and even with THC
present, the animals showed
abstinence symptoms.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Most cannabis users do not become
dependent and do not seek treatment.
Treatment in outpatient programs involves
cognitive-behavioral therapy, relapse
prevention training, and/or motivational
enhancement therapy, but patients are
very vulnerable to relapse.
Some research on medications to relieve
withdrawal symptons has been done.
Figure 14.21 Time course of relapse to first marijuana use after the first 30 days of treatment
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Effects of chronic cannabis use
In young people, amount of cannabis use
is inversely related to educational
performance.
Some research supports the hypothesis
that heavy cannabis use leads to
persistent cognitive deficits, impairing
school performance.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Alternatively, poor school performance
and rejection of mainstream values
such as educational achievement may
increase cannabis use.
Chronic cannabis use can also result in
aimlessness, decreased motivation,
lack of planning, and decreased
productivity—amotivational
syndrome.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Imaging studies suggest that chronic
marijuana use is associated with
several kinds of abnormalities in the
brain.
Several studies have found a significant
relationship between early heavy
marijuana smoking and increased risk
for later development of psychotic
disorders such as schizophrenia.
Box 14.2, Figure A Increased probability of developing psychosis in heavy cannabis users
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Other researchers question some of
these results and suggest other
interpretations of the relationship.
1. Association model—individuals
who are already vulnerable to
developing psychosis have an
increased likelihood of using cannabis
when they are young
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
2. Causal model—heavy use
predisposes individuals to develop
psychosis later in life.
3. Indicator-variable model—one or
more other factors lead jointly to
cannabis use and psychosis
proneness.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Health effects:
There are no reports of death from
overdose.
Smoking marijuana can damage lungs—
smoke contains tar, carcinogens,
carbon monoxide, etc.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
THC has been found to impair resistance
to bacterial and viral infections under
controlled experimental conditions, but
it is not clear yet whether this occurs in
real-life conditions.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
THC may affect reproductive functions:
• Supresses release of LH (luteinizing
hormone).
Other animal work has demonstrated
pregnancy failure, retarded embryonic
development, and even fetal death with
THC administration, but this has not yet
been reported in controlled human
studies.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
In men, regular smoking has been shown
to decrease testosterone levels and
sperm counts.
Smoking during pregnancy: cognitive
deficits, poor school achievement, and
increased risk for tobacco and/or
marijuana use later in life have all been
associated with prenatal marijuana
exposure.
Cannabis Abuse and the Effects of Chronic Cannabis Exposure
Synthetic designer cannabinoids – “K2”
or “Spice.”
Appeared in 2004 on the Internet;
produce several adverse physiological
and psychological effects.
They have been placed under Schedule
I, which bans recreational use.