SAN FRANCISCOMEDICINE - California Society of Addiction ...

Addiction and Recovery
Marijuana Facts
The Risk of Addiction
Timmen L. Cermak, MD
Marijuana is a marvelous story. I
mean that scientifically; more
specifically, neuroscientifically.
It was not until 1960 that Raphael
Mechoulam, an Israeli researcher, was able
to work out the molecular structure of THC,
delta-9-tetrahydrocannabinol—the main
psychoactive ingredient extracted from
the oily resin produced by the cannabis
plant. However, for almost more than three
decades, the mechanism by which THC interacted
with the brain remained a mystery.
Dr. Allyn Howlett paved the way out of
this mystery in 1988 when she first demonstrated
the existence of cannabinoid receptors
in the brain. After that, the new field
of cannabinoid neuroscience took flight.
Two years later, Dr. Miles Herkenham used
a labeled cannabinoid agonist to map the
concentration of what was soon to be called
CB1 receptors (CB2 receptors, discovered
in 1993, are located primarily outside the
CNS) in several species. Then Dr. William
Devane, working in Mechoulam’s lab after
leaving Howlett’s, announced discovery
in 1992 of the first endogenous cannabinoid—anandamide.
The basic research blueprint—extract
the psychoactive substance from a plant’s
oily residue, label it, discover and map
receptor sites within the brain, and then
find the endogenous ligand for those receptors—replicates
the path earlier paved by
opiate researchers. Except the endocannabinoid
system is at least tenfold the size
of the endorphin system. In fact, according
to Mechoulam, “The cannabinoid receptors
are found in higher concentrations than
any other receptor in the brain . . . and the
endocannabinoid system acts essentially in
just about every physiological system that
people have looked into. . . .”
For researchers, the “cannabinoid
story” has shifted radically from marijuana
to the brain, from the question of why marijuana
makes people “high” to the question
of what functions this massive neurochemical
system underlies.
To begin, our endocannabinoids (at
least four different endogenous ligands
have been identified) are neuromodulators,
not neurotransmitters. Rather than
transmit detailed information, endocannabinoids
act in a retrograde fashion at
synapses, reaching back to enhance or
dampen input from incoming neurons.
Rather than being stored in vesicles, like
most neurotransmitters, the endocannabinoids
reside within the neuronal
membrane itself (remember, THC is fat
soluble) and become available as needed
to modulate efferent input.
The endocannabinoid system is tonically
active, meaning that it exhibits a
constant level of ongoing activity that can
be either increased or decreased in order
to modulate a function—appetite, for example.
Anyone who has been in the thrall of
increased cannabinoid stimulation knows
what the “munchies” are—an increased
appetite for comfort food. On the other
hand, decreasing endocannabinoid activity
below its usual tonic level by administering
a cannabinoid antagonist (for example,
SR141716A, or Rimonabant) leads to a loss
of appetite. More strikingly, administering
SR141716A to newborn rat pups in the
first twenty-four hours of life (when the
concentration of endocannabinoids in the
brain is at the highest) leads to a failure to
suckle, and death.
An intriguing window into the overall
value of our endocannabinoid system is
provided by CB1 knockouts—mice genetically
engineered to have no CB1 receptors,
and thus no functioning endocannabinoid
system in the CNS. A variety of interesting
differences exist between CB1 knockouts
and their normal brethren. CB1 knockouts
display hypomotility when put into a maze.
They explore their environment less. They
have better memories. Anyone who has run
a personal experiment with increasing cannabinoid
stimulation might remember the
decline in short-term memory that ensued.
One downside of better memories is that
CB1 knockouts also show decreased forgetting
of aversive memories. For example,
classical conditioning using punishment
is highly resistant to extinction. One might
speculate that veterans with posttraumatic
stress disorder who have an inclination
to use marijuana might be reacting to the
temporary balm it provides for their aversive
memories. Animal studies indicate that
AM404 (an inhibitor of eCB breakdown
and reuptake) may be a more effective
enhancer of extinction.
Perhaps most significant is the increased
mortality that CB1 knockouts
show, not from any single cause but from a
wide variety of normal illnesses. The speculation
is that the endocannabinoid system
continuously modulates a wide array of
physiologic functions, thereby increasing
the flexibility an organism’s responses to
the changing environment. Without this
ongoing capacity to modulate such functions
as memory, pain threshold, appetites,
attention, motor activity, fear/anxiety, and
novelty/familiarity (to name a few), an
animal is restricted to a more narrow range
of physiological and behavioral responses.
Such rigidity leads to a wearing down of the
various organ systems more quickly, and
hence to early mortality.
23 San Francisco Medicine June 2010 www.sfms.org
22 San Francisco Medicine April 2010 www.sfms.org