YSM 85-3

BIOCHEMISTRY
FEATURE
Banned by the U.S. government and legalized by other nations,
praised by some college students and disdained by others, marijuana
is an issue of contention not only in policy writing but also in the
medical sphere. The endocannabinoid system — which regulates the
psychoactive effects of marijuana — is emerging as a new medical
target in pain research and many other areas, such as weight loss and
neurological disorders. However, the stigma associated with cannabis
and cannabinoids leave scientists and doctors in a controversial
conundrum.
Although the endocannabinoid system (ECS) is a relatively
“young” discovery in the world of signaling systems (the term
“endocannabinoid” was coined
in the mid-1990s), it is surprisingly
heavily involved with a
number of our bodily functions
and pathological conditions. This
elaborate network of receptors
and proteins — which includes
endocannabinoids, enzymes, and
the cannabinoid receptors CB1
and CB2 — plays major roles
in our immune function, autonomic
nerve function, memory,
stress response, and appetite.
Research even demonstrates a
clear relationship between altered
endocannabinoid signaling with
cancer, cardiovascular disorders,
eating disorders, and psychiatric
and neurological disorders.
Enticed by the system’s powerful
role in regulating cravings,
mood, pain, and memory, drug
designers have endeavored to
develop drugs that can improve
one’s physical and mental health
despite much controversy. While
some researchers have been successful,
others point out gaps in our knowledge and understanding
of the system. In 2006, the pharmaceutical company Sanofi-Aventis
began selling a new weight-loss drug, Rimonabant, that worked by
targeting CB1 receptors and reducing patients’ appetites. Within six
months, however, the company had received more than 900 reports
of side effects, such as depression and nausea, and the drug was
then pulled from the market. Studies later linked the existence of
a previously undiscovered second receptor, CB2, to these effects.
“It’s against the propagation of life in the long run to interfere
with the central components of appetite,” asserts Dr. Tamas Horvath,
who serves as Chair of the Section of Comparative Medicine and
works as a Professor of Neurobiology and Obstetrics, Gynecology,
and Reproductive Sciences at the Yale School of Medicine. For this
reason, the development of such drugs that target ECS receptors has
The Marijuana Receptors
A New Medical Target?
BY ARASH FEREYDOONI
raised ethical controversies; when we try to manipulate a system as
widespread and effective as the ECS without sufficient understanding,
we can end up with a broad spectrum of unintended effects.
“It is virtually impossible to selectively interfere with either a brain
region or a peripheral organ such as the liver, without having any
other impact on other tissues,” Horvath adds.
Other pharmaceutical companies have tried to develop powerful
painkillers that imitate how the active ingredient in marijuana, delta-
9-tetrahydrocannabinol (THC), reacts with receptors in the body’s
endocannabinoid system. The British company GW Pharmaceuticals
is one of these companies currently seeking FDA approval for their
marijuana mouth spray, Sativex.
GW Pharmaceuticals is attempting
to quell concerns of recreational
drug abuse by utilizing only two
cannabinoid compounds that
could counterbalance each other:
THC and CBD (cannabidiol).
While THC would activate CB1
receptors for pain relief, CBD is
believed to suppress the “high”
feeling that comes as a side effect
of THC. The company also advertises
that Sativex, as a mouth spray,
takes at least an hour to start producing
an effect — a time period
too long to be easily abused by
drug users.
Although the FDA has set strict
guidelines regarding cannabinoid
pharmaceutical drugs, there is
evidence that a policy shift may
soon allow more of these drugs
to appear on the market. In the
1980s, Marinol and Cesamet, two
The ECS is responsible for appetite and award-seeking behavior.
drugs based on synthetic cannabinoids,
were approved for
Courtesy of BBC Science Features
alleviating the nausea and vomiting
for patients undergoing chemotherapy and for stimulating the
appetite of patients with AIDS. Further trials for these drugs have
concentrated on movement disorders such as Parkinson’s syndrome,
chronic pain, dystonia, and multiple sclerosis. Despite claims that
these drugs are based on synthetic compounds and have low risk
of physical or mental dependence, concerns still exist over whether
such cannabinoid-based drugs could or would still be abused for
recreational use.
While developing new drugs targeting the ECS can bring about
groundbreaking medical treatments, the extensive and highly integrated
nature of the ECS has made it very difficult to avoid negatively
affecting the other parts of body. The quest and urge to better
understand the endocannabinoid system needs to be tackled before
we can begin to see the ECS as a common medical target.
www.yalescientific.org April 2012 | Yale Scientific Magazine 27