Canadian Cannabis Coalition

Marijuana, Genes, Medicines And Brain Scans Help
Scientists Find Better Anxiety Treatments

http://www.sciencedaily.com/images/2008/04/080418154959.jpg
This composite image from the 16 study
volunteers' brains shows that the amygdala
was the site of the largest difference in
brain response to emotional images after
volunteers received either THC or placebo.
(Credit: Image courtesy of University of Michigan Health System)

ScienceDaily (Apr. 18, 2008) ? Right now, about half of all people
who take medicine for an anxiety disorder don't get much help from
it. And doctors have no definitive way to predict who will, and who
won't, benefit from each anti-anxiety prescription they write.

But a University of Michigan Medical School researcher and his team
are working to bring more certainty to how doctors and patients
choose anxiety treatments, by probing the connection between brain
activity, genetics and medication.

K. Luan Phan, M.D., and his former University of Chicago colleagues
recently reported intriguing findings from a brain imaging study in
occasional, non-dependent, marijuana users in the Journal of
Neuroscience.

In a placebo-controlled design, they made the findings after giving
the volunteers delta-9-tetrahydrocannabinol (THC), the active
ingredient in marijuana, and exposing them to photographs of
emotional faces, which served as signals of social communication.
The study results, which showed that THC reduces the response to
threat in a brain region called the amygdala, allowed the
researchers to zero in on an area of the brain that might serve as a
good target for new anti-anxiety drugs.

Now, with a new clinical trial that is currently seeking
participants, Phan is searching for more clues as to how anxiety
treatment could be tailored to the individual patient, to give the
best chance that a treatment will work for him or her.

The new study will test a generic form of the drug Zoloft
(sertraline), a selective serotonin reuptake inhibitor (SSRI)
approved by the U.S. Food and Drug Administration for social anxiety
disorder and other anxiety disorders. Both people with social
anxiety disorder and a comparison group of people without anxiety
are needed for brain scanning and genetic testing.

The idea is to see whether variations in the genes for certain brain
receptors and transporters are linked with variations in how a
person's brain reacts to pictures of emotional faces, and variations
in how they respond to the anti-anxiety drug. This information could
lead to an individualized or personalized approach to medical care.

"These two studies are trying to get to the same goal: to find
better treatments for anxiety disorders that affect millions of
Americans and seriously interfere with their functioning," says
Phan, an assistant professor of psychiatry at U-M and the VA Ann
Arbor Healthcare System. "The cannabis study highlights a new avenue
that we need to explore further as we try to develop novel
medications, while the sertraline study will try to find out if we
can tell which patients might or might not respond well, and by what
mechanism, to an already existing medication known to have some
efficacy in treating anxiety disorders."

Phan led the cannabis study at the University of Chicago,
collaborating with Harriet deWit, Ph.D., the director of the Human
Behavioral Pharmacology Laboratory in the Department of Psychiatry
there. Their results are based on brain scans of 16 recreational
marijuana users who agreed to undergo functional magnetic resonance
imaging, or fMRI.

The researchers chose fMRI because it allows them to see in real
time which areas of the brain are most active while a volunteer is
performing a certain task -- for example, viewing a picture of a
human face that is expressing anger or fear, or performing a
decision-making exercise.

That same approach will be used in the new sertraline study, with
two different scans before and after anxiety patients are prescribed
the medication. The healthy volunteers in the study will also have
fMRI scans, though they will not receive the drug. All study
participants must between 18 and 55 years old, and those with
anxiety disorders must not be taking any other medication that could
be affecting the brain in order to qualify to enter the study.

The cannabis study used THC, and a placebo caplet that looked
exactly like the THC caplet. The researchers found that when the
marijuana users received THC, their brain's response
to "threatening" faces was less than it was when they received a
placebo.

The difference in response was seen in an area of the brain called
the amygdala, which is a hub for the brain's ability to process
signs of danger or warning, and to decide how to respond. But there
were no differences between THC and placebo in the areas of the
brain that process non-emotional visual signals or govern body
movement -- suggesting that THC had a specific effect on a specific
brain region and on a specific task of processing fear. Other
researchers have shown this to be a region that's rich in a receptor
called CB1, part of the brain's "cannabinoid" system.

The human brain produces compounds called endocannabinoids that act
on these receptors, and are involved in anxiety and fear-learning,
or the learning of which threats to be afraid of. But little has
been known about the effect of THC, an exogenous cannabinoid, on the
brain's own system.

For ethical reasons, the researchers did not give THC to non-
marijuana users, and the study was small. But the findings in the
study volunteers suggest that THC and other compounds that act on
the CB1 receptors in the amygdala could be fruitful targets for new
anti-anxiety medicines. Phan notes that rimonabant, a smoking-
cessation and weight-loss drug not yet available in the United
States for clinical use, also acts on the CB1 receptor.

Understanding how drugs such as marijuana affect the brain may also
help reveal more about why people become addicted to illicit drugs
or abuse certain prescription drugs, Phan notes. Some individuals
may be using illicit drugs and misusing prescribed drugs to
alleviate their anxiety. He hopes to investigate this issue further
by studying people who have used prescription pain drugs
recreationally (such as oxycodone), using new funding from the
National Institutes of Health.

The THC study links three key domains of human behavior: a specific
region of the brain, the function of that area, and a neurochemical
agent (THC) that appears to act on them. The new sertraline study
will take it one step further, by looking at genetics too.
Specifically, Phan and his colleagues will look for variations
("functional polymorphisms") among several genes in individual
subjects. Key among them is the gene (5-HTTLPR) that encodes the
serotonin transporter protein that transports the neurotransmitter
serotonin in and out of brain cells. Serotonin has long been known
to be involved in depression and anxiety, and indeed most modern
antidepressant and anti-anxiety drugs (such as SSRIs) work on this
transporter.

Journal reference: Journal of Neuroscience, March 5, 2008, Vol. 28,
No. 10, 2313-2319

Adapted from materials provided by University of Michigan Health
System.

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