Pubdate: Sun, 08 Mar 2015
Source: New York Times (NY)
Copyright: 2015 The New York Times Company
Contact: http://www.nytimes.com/ref/membercenter/help/lettertoeditor.html
Website: http://www.nytimes.com/
Details: http://www.mapinc.org/media/298
Author: Richard A. Friedman
Note: Richard A. Friedman is a professor of clinical psychiatry at 
Weill Cornell Medical College.

THE FEEL-GOOD GENE

CHANCES are that everyone on this planet has experienced anxiety, 
that distinct sense of unease and foreboding.

Most of us probably assume that anxiety always has a psychological trigger.

Yet clinicians have long known that there are plenty of people who 
experience anxiety in the absence of any danger or stress and haven't 
a clue why they feel distressed. Despite years of psychotherapy, many 
experience little or no relief. It's as if they suffer from a mental 
state that has no psychological origin or meaning, a notion that 
would seem heretical to many therapists, particularly psychoanalysts.

Recent neuroscience research explains why, in part, this may be the 
case. For the first time, scientists have demonstrated that a genetic 
variation in the brain makes some people inherently less anxious, and 
more able to forget fearful and unpleasant experiences. This lucky 
genetic mutation produces higher levels of anandamide - the so-called 
bliss molecule and our own natural marijuana - in our brains.

In short, some people are prone to be less anxious simply because 
they won the genetic sweepstakes and randomly got a genetic mutation 
that has nothing at all to do with strength of character. About 20 
percent of adult Americans have this mutation. Those who do may also 
be less likely to become addicted to marijuana and, possibly, other 
drugs - presumably because they don't need the calming effects that 
marijuana provides.

One patient of mine, a man in his late 40s, came to see me because he 
was depressed and lethargic. He told me at our first meeting that he 
had been using cannabis almost daily for at least the past 15 years. 
"It became a way of life," he explained. "Things are more 
interesting, and I can tolerate disappointments without getting too upset."

But it was also clear that he was cognitively dulled by his chronic 
marijuana use and though it was effective in helping him control his 
anxiety, it impaired his ability to work.

When he finally stopped using cannabis, he was markedly more alert, 
reactive and, alas, more anxious: "I'm definitely more alive, and 
sharper, but I'm more nervous and irritable, too."

Clearly, my patient had been using cannabis to effectively quell his 
chronic anxiety, which had been immune to years of insight-oriented 
psychotherapy. Of course, some might argue that his use of cannabis 
could have rendered his therapy less effective because, the thinking 
goes, you can't really work through certain psychic conflicts if you 
cannot tolerate being anxious. Perhaps there is some truth to this, 
although my patient had a surfeit of anxiety that even cannabis could 
not entirely eradicate.

But there is another way of understanding my patient's anxiety and 
cannabis use. The endocannabinoid system, so named because the active 
drug in cannabis, THC, is closely related to the brain's own 
anandamide, is the target of marijuana and has long been implicated 
in anxiety. It exists throughout the animal kingdom, though one would 
be hard-pressed to find a nonhuman animal clever - or foolish - 
enough to eat solely for the purpose of stimulating its own receptors 
with cannabis.The major naturally occurring cannabinoid in our brain 
is anandamide, something our bodies synthesize. Anandamide is, aptly, 
taken from the Sanskrit word ananda, meaning bliss because, when it 
binds to the cannabinoid receptor, it has a calming effect. Continue 
reading the main story

We all have anandamide, but those who have won the lucky gene have 
more of it because they have less of an enzyme called FAAH, which 
deactivates anandamide. It is a mutation in the FAAH gene that leads 
to more of the bliss molecule anandamide bathing the brain.

People with the variant FAAH gene are less anxious and are thus less 
inclined to like marijuana. They actually experience a decrease in 
happiness when smoking marijuana, compared with those with the normal 
FAAH gene, who find it pleasurable. If you naturally have more of the 
real thing you understandably have little use for marijuana.

Studies show that those without the variant gene suffer more severe 
withdrawal when they stop using cannabis. Here, at last, is an 
example of a mutation that confers an advantage: lower anxiety and 
protection against cannabis dependence - and possibly to addiction to 
some other drugs, too.

For example, one community-based study of almost 2,100 healthy 
volunteers found that people with two copies of the mutant gene had 
roughly half the rate (11 percent) of cannabis dependence than those 
with one or no mutant gene (26 percent).

Obviously, there is more to abstinence than grit and moral fiber: 
Having a double dose of a gene mutation gives you a big advantage in 
being able to "just say no."

Interestingly, the frequency of the advantageous FAAH mutation 
differs widely among ethnic groups. According to recent data from the 
HapMap, an international project that studies genetic similarities 
and differences in humans, roughly 21 percent of Americans of 
European descent, 14 percent of Han Chinese living in China and 45 
percent of Yoruban Nigerians have been found to carry this gene variant.

SO effective is cannabis in relieving unpleasant mental states and 
inducing happiness that it is hardly surprising that it is the most 
frequently used illicit drug in the United States - though it may be 
only a matter of time before it's legal throughout the states. 
Forty-four percent of Americans age 12 and older report having used 
marijuana at some point during their lives, according to the National 
Institute on Drug Abuse.

It's also likely that these recent cannabinoid findings are a small 
part of the larger story that is not yet totally clear. For example, 
there is evidence that a genetic variation in the mu opioid receptor, 
the target of morphine, OxyContin and other opiates, has a protective 
effect against opiate addiction.

Still, does this cannabinoid mutation simply correlate with less 
anxiety, and less addiction to marijuana - or does it cause them?

To answer that question, Dr. Francis S. Lee, a professor of 
psychiatry, and Iva Dincheva, a researcher, both at Weill Cornell 
Medical College, along with colleagues at the University of Calgary 
and elsewhere, took the human FAAH variant gene and inserted it into 
mice, where they could see the gene in action and study its specific 
effects. They simultaneously studied a group of human subjects with 
the variant FAAH gene. (The study was published last week in Nature 
Communications.)

Sure enough, these "humanized" mice that got the variant gene were 
less anxious, as evidenced by their spending more time in the open 
section of a maze. (More anxious mice, in contrast, prefer the safety 
of the enclosed arms of the maze.) And, just like people with this 
same gene, they showed similar changes in the neural circuits 
involved in anxiety and fear. Specifically, they had greater 
connectivity between the prefrontal cortex, the executive control 
center, and the amygdala, which is critical to processing fear, than 
the animals with the normal FAAH gene. A stronger connection between 
these two brain regions is known to predict lower anxiety and greater 
emotional control.

The benefits of this cannabinoid mutation don't stop there. When Dr. 
Lee fear-conditioned the mice and human subjects by teaching them to 
associate a previously neutral stimulus with a noxious one, like a 
noise or electric shock, all the subjects - regardless of the genetic 
variant - learned the fearful associations equally well.

But when he taught the same subjects that the previously dangerous 
cue was now safe, by repeatedly presenting this stimulus without the 
noxious one - a process called fear extinction - the results were 
startling. Both mice and humans with the cannabinoid mutation showed 
enhanced fear extinction - that is, they learned more efficiently how 
to be unafraid.

So it seems that nature has designed us all to be on high alert for 
danger: We all learn to be afraid of new threats with equal facility. 
But some of us, like those with this cannabinoid mutation, forget 
about previous dangers more easily and move around in the world with 
less anxiety. This seems like a good deal for the species: We're 
protected by those who are anxious and vigilant and enriched by those 
who are more carefree and exploratory.

Aside from insight into anxiety, these findings also suggest 
intriguing new therapeutic targets for drug abuse in general. That's 
because the cannabinoid circuit directly influences the dopamine 
reward pathway, which is the shared target of commonly abused drugs, 
like cocaine, opiates and alcohol. Thus, it is possible that a 
medication that targets the endocannabinoid system could be 
beneficial in treating addiction to cannabis, and other drugs, too.

In a broader sense, Dr. Lee's study has important implications for 
personalized medicine. Imagine you are a soldier returning from war 
with PTSD. With a simple blood test looking at gene variants, we 
could discover whether you were biologically adept at fear 
extinction, which is essentially the basis of exposure therapy for 
PTSD. If you had a mutation that reduced your ability to extinguish 
fear, your therapist would know you might just need more exposure - 
more treatment sessions - to recover. Or, perhaps a different therapy 
altogether that doesn't rely on exposure, like interpersonal therapy, 
or medication.

By now you must be wondering why on earth we have cannabinoid 
receptors in our heads in the first place. In fact, they are among 
the most numerous receptors in our brains. And while we're on the 
subject, we also have opioid receptors and nicotine receptors that 
are lock and key with opiates and nicotine. The body makes its own 
endogenous "keys" for all these receptors. As for the benzodiazepine 
receptor, the brain manufactures the calming neurotransmitter GABA, 
which binds very close to the benzodiazepine site, the place where 
anti-anxiety drugs like Valium and Klonopin bind. Well, if you 
believe in intelligent design (count me out), you would have to 
credit the creator with a really wicked sense of humor to have 
hard-wired our brains for such varied temptations, to say nothing of 
the fact that, neurobiologically speaking, some of us are barely 
tempted at all. It's all very unfair. Continue reading the main story 
Continue reading the main story Continue reading the main story

None of these studies should be taken to mean that biology calls all 
the shots. Far from it. The environment plays a critical role and can 
sometimes even trump genetics. For example, primates who are 
genetically at low risk of drug abuse can easily be converted to 
compulsive drug users just by exposing them to cocaine or by putting 
them in crowded, stressful situations.

Dr. Michael A. Nader and his colleagues at Wake Forest University 
discovered that monkeys, just like people, with low levels of 
dopamine type-2, or D2, receptors in the brain's reward center were 
more likely to self-administer cocaine than those with high receptor 
levels. All drugs of abuse cause the release of dopamine in the 
reward circuit, which triggers a sense of pleasure and craving.

But when he exposed the animals who were genetically less prone to 
use cocaine, they lost D2 receptors and started to self-administer 
the drug just like the high-risk monkeys.

Strikingly, the effect was reversible: With abstinence, 60 percent of 
the primates' D2 receptor levels normalized. The clear implication is 
that probably anyone - regardless of genetic risk - can become 
addicted or abstinent in the right environment.

The fact is that we are all walking around with a random and totally 
unfair assortment of genetic variants that make us more or less 
content, anxious, depressed or prone to use drugs. Some people might 
find it a relief to discover that they had a genetic variant that 
made them naturally more anxious - that they were wired for anxiety, 
not weak - even if right now there is no exact fix. My patient 
benefited greatly from antidepressant medication and meditation. But 
psychotropic medications, therapy and relaxation techniques don't 
help everyone, so what's wrong with using marijuana to treat anxiety?

The problem is that cannabis swamps and overpowers the brain's 
cannabinoid system, and there is evidence that chronic use may not 
just relieve anxiety but interfere with learning and memory. What we 
really need is a drug that can boost anandamide - our bliss molecule 
- - for those who are genetically disadvantaged. Stay tuned.
- ---
MAP posted-by: Jay Bergstrom