Drugs for Therapeutic Forgetting? – Forget about it.

Over that past decade, there has been a great deal of interest in the prospect that we might be able to edit unpleasant memories (a phenomenon dubbed therapeutic forgetting) by capitalizing upon the phenomenon of reconsolidation.  The basic idea is this: although memories are stable for years, when we recall a memory it becomes labile.  Once the memory is transformed into this more flexible state, it can be modified by subsequent experience.  The memory is not lost, but becomes reconsolidated (most probably during the subsequent night’s sleep); in this way, new experiences are integrated with old ones, providing a mechanism by which experiences throughout the lifetime can be in amalgamated in meaningful fashion.

Spearheaded by studies from Joseph Le Doux’s laboratory, several groups have reasoned that if one were to induce individuals to recall problematic memories and then interfere with reconsolidation using pharmacological means, we might be able to specifically amend our memories of past events.  From a therapeutic perspective, this would be most useful in treating patients with post-traumatic stress disorder (PTSD) in which the memories of certain emotionally charged events become so troublesome that they have outsized effects on the quality of life.  The problem has been with the potential side effects of the pharmacological approach – protein synthesis inhibitors, partial NMDA receptor agonists, viral vectors with toxins as the payload, & beta-adrenergic receptor blockers have all been shown to be effective in laboratory experiments, but, with the notable exception of beta-blockers, none are really suitable for use in the clinical setting.

But a good idea does not lay fallow for long, and a collaboration between Elizabeth Phelps and Joe LeDoux’s groups has again advanced the field in impressive fashion. Following up on recent observations in laboratory animals, these groups report in Nature that a simple manipulation, extinction training, reduces fear memory in humans.  The essence of the experiment is this: humans are exposed to a stimulus (a blue square, for example) which is coupled to something aversive (a mild shock on the wrist).  The next day, when subjects were once again exposed to the blue square alone, they showed anxiety responses, as if they were expecting the shock.  According to the reconsolidation hypothesis, re-exposing people to this stimulus should make the memory labile.  To test this, ten minutes later (when the memory was still quite plastic), they repeatedly exposed the subjects to the blue square without the shock, a form of extinction training.  On the third day, when these subject were once again tested by exposing them to the blue square alone, they did not show anxiety responses.  What is most remarkable is that they defined a narrow time window in which extinction training was effective; if they allowed 6 hours to transpire on the second day between re-exposing the subjects and commencement of extinction training, the manipulation was ineffective and subjects were still anxious on the third day when the ominous blue square reappeared.

As is noted in the accompanying commentary, these results derive from very well-controlled laboratory experiments and we don’t yet know whether they will translate into the more complex clinical situation of PTSD.  But the interesting question from the perspective of neuroethics is this: does it really make the process of therapeutic forgetting any less worrisome when the manipulation is behavioural rather than pharmacological?  I would suggest that many people would say yes.   Certainly the issue of safety is sidestepped, but I suspect that this is not the essence of most people’s concerns.  Rather, I believe that we have an aversion to using chemicals to manipulate our brains (except for hedonist pursuits that fall under the umbrella of recreational drug use) while we seem rather comfortable with manipulating our brains by behavioural measures.  One plausible hypothesis is that the behavioral manipulation somehow seems more natural to us.  But as any keen observer of neuroscience knows (and indeed, as the reconsolidation hypothesis demonstrates), every experience that we have changes the underlying chemical makeup of our brains. So is it so different after all?

[For a thorough and thoughtful discussion of the ethical and legal issues involved in therapeutic forgetting, I highly recommend Adam Kolber’s article on the subject.]

[Update:  I see that both Time and the Guardian have short articles on this paper as well.]

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One thought on “Drugs for Therapeutic Forgetting? – Forget about it.

  1. “as any keen observer of neuroscience knows (and indeed, as the reconsolidation hypothesis demonstrates), every experience that we have changes the underlying chemical makeup of our brains. So is it so different after all?”

    Right on! Neil Levy also makes this point very well in his book, “Neuroethics: Challenges for the 21st Century,” in his chapter on the presumption against direct manipulation. He has a thought experiment involving two depressed patients, one who takes an anti-depressant and one who starts an exercise program, both with the goal of altering their neurochemistry, and argues that we shouldn’t think of them differently, at least with regard to the stock criticisms against direct manipulation of the brain. I highly recommend it.

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