Billy R. Martin, Ph.D., Professor, Medical College of
Virginia
National Conference on Marijuana Use: Conference Summary
Prevention, Treatment, and Research DAY 1 - July 19, 1995
I have been researching the effects of marijuana’s
principal psychoactive ingredient, delta-9-tetrahydrocannabinol (THC) for 22 years. My
presentation today will be in three parts: about marijuana and what it is, marijuana and
brain mechanisms, and an exciting new marijuana dependence model.
Marijuana contains more than 400 compounds, more than 60
cannabinoids, and many other ingredients. Its potency is due to the concentration of THC,
which varies widely among different batches or samples and different forms of marijuana.
Comparisons of THC concentrations in confiscated samples of loose
marijuana, kilo bricks, buds, sinsemilla (the buds of unpollinated marijuana plants),
hashish, and hash oil over the last 20 years show that after a rise in potency about 10
years ago, average THC levels have remained relatively constant.
Marijuana intoxication or a subjective high may include an
altered state of consciousness, mild euphoria, relaxation, perceptual alterations, time
distortion, intensification of ordinary sensory experiences, and/or increased sociability.
Unpleasant psychological reactions can be anxiety, depression, panic, delusions, and/or
hallucinations. Cognitive functions such as impaired short-term memory, disruption of
mental activity, and motor functions like altered reaction time and disruption of
coordination can result from marijuana intoxication. Analgesia, sedation, excitation,
hypothermia, and immobility or catalepsy are some of the effects of THC revealed in animal
studies of marijuana intoxication.
Recent major research breakthroughs, such as identifying
marijuana receptors in the brain, have allowed scientists to learn more about how
marijuana affects the brain and how it alters brain functions. These receptors are
specific for cannabinoids, they belong to a family of brain receptors, they are in very
high density in the brain, and their levels change during tolerance development. They are
abundant in relevant areas of the brain that are associated with altered levels of
cognition and the interruption of normal motor function and coordination. Much of the
recent research uses highly potent analogs of THC that produce the same pharmacological
effects as THC.
The recent discovery of anandamide, an endogenous
(internally produced) cannabinoid ligand (molecule) that binds with marijuana receptors
just as THC does, has opened the door to more scientific inquiry about marijuana use.
Anandamide is naturally present in the brain, produces THC-like effects, and is
synthesized and metabolized in the brain. The following unanswered questions remain: What
is the normal physiological role of endogenous cannabinoids? What are the consequences of
high-potency marijuana? What is the result of chronic marijuana use?
Our research findings indicate that marijuana can produce
dependence. We employ standard, proven methods that have been used to demonstrate
dependence on other drugs of abuse. Many drugs that induce a profound tolerance produce an
accompany-ing development of dependence. Marijuana induces such a profound tolerance and
would be an exception if it did not produce dependence.
Animal models for testing for drug dependence include
abrupt withdrawal and precipitated withdrawal. In the former, an animal is continuously
exposed to a drug, then drug administration is stopped abruptly and withdrawal symptoms
are observed. In the latter, an animal is continuously exposed to a drug, then treated
with an antagonist or blocker and withdrawal symptoms are observed. An antagonist
immediately blocks the drug action when administered. In the past, there was not an
antagonist available for marijuana, so precipitated withdrawal studies could not be done.
Last year, a French drug company developed a specific
antagonist that precipitates withdrawal from THC. My colleagues and I have been able to
use this THC antagonist to develop an exciting new marijuana dependence model. Preliminary
studies using high doses of THC followed by the antagonist have demonstrated withdrawal
symptoms in both rats and mice that are consistent with animal studies of other addictive
drugs. A very dramatic response to the dose was exhibited in these and repeated studies
with low doses of THC. Marijuana dependence is related to dose or quantity used and
frequency of exposure.
The availability of a functional experimental model for
marijuana dependence allows for the systematic study of chronic exposure to marijuana and
for the development of treatment approaches for people who become compulsive marijuana
users.
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