or banish your addictions with the help of memory-boosting pills. Jessica Hamzelou faces her own phobia to find out more
IT’S happening again. My heart starts pounding and my pulse races. I can feel my face flush and my palms start to sweat. It is all I can do to prevent myself from breaking into a full-blown panic attack. And yet I’m not in any real danger. I’m just at the top of an escalator, making my way down to a London Underground rail platform, along with hundreds of other Londoners who don’t seem phased in the slightest – but the sight of the drop below me is the stuff of my nightmares. This scenario will sound familiar to the many other people with phobias. All it takes is a worrying thought or glimpse – whether of a steep drop or a spider’s web – for the mind and body to race into panicked overdrive. These fears are difficult to conquer, largely because the best way of getting over a phobia is to expose yourself to your fear many times over. But there may be a short cut. Drugs that work to boost learning may help someone with a phobia to “detrain their brain”, losing the fearful associations that fuel their panic. This approach is also showing promise for a host of other problems – from chemical and gambling addictions to obsessive nail-biting. In a bid to find out if it really works, I head to West Virginia to take part in a trial. The brain’s extraordinary ability to pick up new memories and forge associations is so well celebrated that its dark side is often neglected. In the case of a phobia, it may have been an unpleasant experience that once triggered a panicked response to spiders, mice or, for me, heights, leading the feelings to resurge whenever we see the relevant cue. Former drug addicts have similarly learned responses when they see something that reminds them of their habit: the sight of rolled-up bank notes for a cocaine user, for instance. So how do we overcome such deep-seated associations? One answer is exposure therapy, a treatment primarily used to deal with anxiety and phobias. In those initial studies, people gradually expose themselves to increasingly anxiety-triggering situations – called a “fear hierarchy” – until they feel at ease with them. In my case, that would involve scaling a series of ever greater heights. As the individual becomes more comfortable with each situation, they create a new memory – one that links the cue with reduced feelings of anxiety, rather than the sensations that mark the onset of a panic attack. This process is called extinction learning. Unfortunately, while it is relatively easy to create a fear-based memory, expunging that fear is pretty hard work. Each of those exposure trials will probably involve a great deal of stress and anxiety, leading some psychotherapists to conclude that the treatment is unethical. For that reason, neuroscientists have been looking for new ways to speed up extinction learning. One such avenue is the use of “cognitive enhancers”. One of the most promising contenders is an antibiotic originally used to treat tuberculosis. Apart from its action on germs, D-cycloserine, or DCS, also acts on neurons. The drug slots into part of the “NMDA receptor” – a site that seems to modulate the neurons’ ability to adjust their signalling in response to events. This tuning of a neuron’s firing is thought to be one of the key ways the brain stores memories, and at very low doses, DCS appears to boost that process, improving our ability to learn. In 2004, Kerry Ressler at Emory University in Atlanta, Georgia, and his colleagues were among the first teams to test whether DCS could also help people with phobias. They performed a pilot trial on 28 people undergoing exposure therapy for acrophobia – a fear of heights. Sure enough, they found that those given a small amount of DCS alongside their therapy were able to reduce their phobia to a greater extent than those given a placebo. Since then, other groups have replicated the finding in many more trials. Future research may show ways to refine the method still further. It still takes a long time to accomplish even one of the steps on a person’s fear hierarchy, says Cristian Sirbu, a behavioural scientist and psychologist at West Virginia University in Charleston. “You end up with a patient feeling that they failed,” he says. Instead, he thinks that DCS may make it possible to tackle the problem in a single 3-hour session, which is long enough to make real headway and end with a feeling of satisfaction. To find out if Sirbu’s approach could work for me and others like me, and if a dose of DCS could boost the effects, I landed in Charleston to take part in a trial. The trial started with a battery of tests. To get a good handle on my phobia, Sirbu and his colleague interviewed me before giving me some physical tests. First, the pair hooked me up to electrodes to measure my heart rate and fingertip sweatiness, before sitting me in front of a video of a pair of gardeners walking around a rose garden, discussing its merits. The team were trying to get an idea of how my body functioned in a relaxed state, before we moved on to actual heights. With the electrodes still attached, I was asked to approach a second-storey balcony. The team recorded increases in heart rate and sweating as I started to panic – business as usual for me. The exciting part of the study kicked off a week later, when I am given a tablet to swallow – I don’t know whether it is DCS or merely a sugar pill – before starting my 3-hour therapy session. The therapy itself is a gruelling experience to say the least. After walking down a windowed corridor on the fifth floor of a building, Sirbu and I head to the hospital’s stairwell. With a huge visible drop to one side of me, it is terrifying. Our voices echo and I try to focus on the dust bunnies lying on each step. But after an exhausting 3 hours I start to have a full-blown panic attack which prevents me from reaching Sirbu’s goal of climbing two floors up the staircase. Rewrite or delete What went wrong? Phobias come in different flavours, and more intense fears can take more work to overcome. Because I needed another session, Sirbu pulled me out of the clinical trial. He then tells me that I had taken the active drug, not the placebo. It is a disappointing result, particularly after hearing about Sirbu’s promising results with other trial participants, all of whom experienced some kind of benefit from the session, he tells me. Ultimately, trying to erase a fear response in a single trial may just be too ambitious for someone with a phobia as extreme as mine. What is more Merel Kindt, who studies anxiety disorders at the University of Amsterdam in the Netherlands, is sceptical DAVID SEYMOUR/MAGNUM Can we return to the fearless bliss of childhood? that its benefits would last. She points out that although Sirbu’s approach attempts to lay down calmer associations, it doesn’t directly undo the fearful response that is also embedded in our memories, so there’s always a chance to relapse. Indeed, since the therapy had failed while I took the cognitive enhancer, I am concerned that I may have instead laid down even more stressful memories – a potential problem with the method that has troubled some researchers. But there may be another way. Rather than simply trying to overlay the fearful associations with a new one, Kindt is instead trying to alter them at their source. To do so, her method targets an entirely different pathway from the trials using DCS. It is based on the idea that every time we access a memory, be it of a specific recollection or a learned reaction, we temporarily put it in a fragile state. Normally, the updated memory is then re-consolidated by the formation of new proteins that make the necessary synaptic changes, and if stress hormones like adrenaline are washing around the body – as is often the case during the fearful reactions of someone gripped by a phobia – the original memory’s emotional force is maintained. But a beta-blocker drug called propranolol can block the adrenaline from binding to the neurons, which Kindt hopes will interfere with the process to stop the emotional trauma associated with the cue from being reinforced. “We don’t erase the memory, but we can erase the learned fear response,” she says. A similar approach is already in clinical trials to soothe the fearful flashbacks that haunt people with post-traumatic stress disorder. Kindt’s team is currently testing its effectiveness with arachnophobia – by giving people propranolol while they look at spiders, for example. “It’s very successful,” she claims. “The participants said they still didn’t like spiders, but they were able to approach a tarantula.” Kindt, who is preparing the findings for publication, says the benefit was still there when she checked three months later. As the work to treat phobias gains momentum, others are looking at whether the same strategies could work with addictions. After all, phobias and addictions share some similarities. “They are both habitual, emotional, reflexive responses,” says Ressler. Here, the idea is to expose a person to a “trigger environment” associated with taking a drug. That might be the sight of a cigarette for instance. But in therapy sessions, the individual isn’t allowed their substance of choice, leading them to learn how to resist the urge. Elizabeth Santa Ana, now at the Medical University of South Carolina in Charleston, has tested whether DCS could boost this method, using a group of smokers. “People would sit in a room with a packet of their favourite cigarettes, take a cigarette and hold it up to their mouth, but not smoke it,” she says. At the same time, Santa Ana taught them coping skills, and encouraged them with guided imagery. “For example, I would ask them to imagine having tar all over their bodies, and then imagine being able to breathe freely once they’d stopped smoking,” she says. Forgotten cravings In the group of 25 participants, 13 were given a small dose of DCS during their time in the lab, while the rest took a placebo. For the preliminary study, the team did not ask the participants to give up smoking. Instead, they measured the smokers’ cravings a week after the therapy – by asking them how great an urge to smoke they felt, and measuring how much they sweated when faced with a cigarette they were not supposed to light. The team found that people who had been given a dose of DCS exhibited a reduced sweating response to smoking cues, and also reported a lower desire to smoke. “There were both objective and subjective differences between the two groups,” says Santa Ana. “They were promising findings.” Clearly, it will take more trials to find out if the approach actually helps people quit smoking for good. In any case, it looks likely that other strategies would be needed to extinguish cravings for other drugs; trials of cocaine-addicted people using DCS did not report reduced desire for a hit, for instance. RIGHT: PATRICK MOURRAL/PICTURETANK; FAR RIGHT: ROBERTO BOCCIARDO/AURORA Propranolol – the beta-blocker that Kindt was using to “destabilise” the learned responses of people with arachnophobia – may be more fruitful. In a study last year, 50 people addicted to cocaine watched videos of people taking the drug. Half of the group had been given a small dose of propranolol immediately after watching the films. A day later, they were asked to watch the films again, but they reported that the intensity of their cravings had fallen significantly more than the control group. The participants also showed a reduced physiological response to the cues. With more sessions, it may therefore be possible to cut the long-term risk of relapse. One of the reasons that addictive cravings are particularly difficult to target is that the addictions themselves can make long-lasting changes to brain chemistry. When people hooked on drugs like cocaine attempt to withdraw from the substance, they experience a drop in brain levels of glutamate – a neurotransmitter that acts to fire up neurons. This imbalance damages communication between the decision-making prefrontal cortex, and the nucleus accumbens – the region involved in pleasure-seeking and reward-learning, potentially explaining why people with addictions find it so difficult to develop the neural pathways necessary to reverse their habits and control their cravings. For this reason, some teams are turning to supplements like n-acetyl cysteine (NAC), which seems to help return levels of glutamate to their normal levels. So far, NAC has shown promise in studies that reversed the drugseeking behaviours of rats addicted to cocaine and heroin. In addition, a series of small trials has shown that NAC also reduces craving in Old habits die hard – unless you get a memory boost Spiders improve on acquaintance people who are still using cocaine. People who were considered to have a problematic dependency on cannabis, meanwhile, were more than twice as likely to show no signs of drug use in a urine test after taking NAC for eight weeks, compared to those taking a placebo. The treatment has also shown positive results for gambling addicts and chronic nail-biters. It is important to note that the NAC treatments did not involve explicit forms of exposure therapy however – rather, the participants were learning to cope with their cravings as they went about their daily lives. So it would be interesting to know what the results with NAC would be like if combined with sessions with a therapist that directly aimed to extinguish the responses to drug cues. Some research groups are aiming to test the possibility. It is still early days. The disappointing results of my trial are enough to convince me that these would-be treatments for phobias and addiction aren’t miracle cures. For most people, changing unwanted habits or reactions will involve dedication and perseverance. And since much of the research into drugs such as DCS have been primarily pilot studies, it will be important to see if similar results are found in bigger clinical trials. But if just one of these possible treatments comes up trumps, it could change many blighted lives. As it is, I’m going to have to trust that good things come to those who wait. Although the “flash therapy” for my phobia did not work for me, I’m now trying a more drawn-out version of exposure therapy. It’s hard going, but right now I’m four steps through my 10-step programme and happy to say that I’m already reaching new heights. ■
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