The feel-good gene
Those of us who don’t have this natural bliss are more likely to be anxious and to self-medicate
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. 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 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 anx- ious 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, 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. 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.
Some of us forget about previous dangers more easily