Chapter 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.
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.
• Figure 14.1 Poster advertising the 1936 film Reefer Madness
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
Hemp also contains 70 unique compounds known as cannabinoids, plus more than 400 other identified
The psychoactive compound Δ -tetrahydrocannabinol (THC), accounts for the use of cannabis as a drug.
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 hollowed-out cigars called “blunts.”
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”).
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
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.
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.
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 -tetrahydro-cannabinol (THC)
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
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
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. Basic Pharmacology of Marijuana – Mechanisms of Action
A cannabinoid receptor in the CNS was identified in 1988.
Receptors occur in many brain areas.
CB 1s the receptor found in the CNS.
CB 2ccurs 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
Cannabinoid receptors are metabotropic; they work via G proteins to inhibit cAMP formation, inhibit
voltage-sensitive Ca channels, and open K channels.
CB 1eceptors are located on axon terminals. By activating these presynaptic receptors, cannabinoids can
inhibit the release of many neurotransmitters.
Synthetic cannabinoid agonists and antagonists have been developed for research and potential
THC given to mice induces reduced locomotor activity, hypothermia, catelepsy, and hypoalgesia—
mediated through CB rec1ptors.
CB 1eceptors also play an important role in the reward system.
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 CB rece1tors are responsible for memory impairment
Other studies have shown that cannabinoids inhibit the induction of long-term potentiation (LTP) in the
hippocampal CA1 area.
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. Two main endocannabinoids have been found: arachidonoyl ethanolamide (AEA), or anandamide, and
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-
They are synthesized and released in response to depolarization of the postsynaptic cell due to the
influx of Ca .
The endocannabinoids then cross the synaptic cleft, activate CB recept1rs on the nerve terminal, and
inhibit Ca -mediated neurotransmitter release from the terminal.
• Figure 14.10 Retrograde signaling by endocannabinoids
To determine the roles of anandamide and 2-AG, researchers use the the CB receptor antagonist
rimonabant, and CB and1CB knock2ut mice.
Pain perception: both approaches produce mice with hyperalgesia (increased pain sensitivity).
Cannabinoid drugs have been used to treat pain and other medical conditions.
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 CB re1eptors are widely expressed in the neural circuitry of the human brain
that regulates mood
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.
Endocannabinoids enhance the incentive motivational properties of food and food-mediated reward.
CB 1eceptor antagonists reduce food consumption in animals and human subjects.
AM6545, a peripherally-acting CB ant1gonist may be useful in treating obesity.
• Figure 14.11 Food intake and body weight gain are reduced in rats
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. CB knocko1t mice do not
show normal extinction of the freezing response.
• Figure 14.12 Role of the endocannabinoid system in extinction of auditory fear conditioning
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 us