From Mouse to Man

What the latest basic science research is telling us about the human mind

Posttraumatic Stress Disorder and Cannabis. A Potted History

Can cannabis erase bad memories? The science behind the headlines.
"....because I can't forget no matter how hard I try.........."
Corporal Cloy Richards, PTSD sufferer.

Cannabis has often been proposed to treat posttraumatic stress disorder (PTSD) and rates of marijuana use are significantly higher in PTSD sufferers. However like all medical marijuana issues it's controversial and complicated. I will try and explain some of the science behind the issue.

The basic rationale is this; a defining feature of PTSD is that sufferers cannot "forget" a traumatic event such as combat or rape. It is well established that cannabis use impairs certain types of memory and may help sufferers "forget". Additionally cannabis often reduces anxiety and promotes sleep, both of which are beneficial for PTSD where elevated general anxiety and sleep disturbances are very common.

Cannabis acts upon receptors in the brain called, appropriately enough, cannabinoid receptors. The first and best described of these is called CB1, or cannabinoid receptor-1. CB1 is found throughout the brain. These receptors don't exist to get people high! What this means is that there are substances produced naturally by the brain, called endocannabinoids, that act at cannabinoid receptors.

The best described endocannabinoids are called anandamide and 2-arachidonyl glycerol (2-AG). These endocannabinoids are flighty molecules, they are rapidly synthesized only when required and don't stick around for long, being swiftly broken down by an enzyme by the name of "fatty acid aminohydrolase", less tongue-twistingly known as FAAH. Endocannabinoids are involved in many biological processes including appetite regulation, pain, anxiety, mood, nausea and blood pressure. All of which are also affected by marijuana.

One of the most interesting things these endocannabinoids appear to do, according to research in rats and mice, is stimulate the ability to forget about bad things. The basic research paradigm used is called "fear conditioning" and works on the same principle as Pavlov's dogs; rodents are played a sound, usually a beep, just before a very slight electric shock. This shock, much like a threat in the wild, causes the animals to freeze in their tracks. Although the shock is mild and brief, the animals obviously don't like it and learn very quickly that the beep means a shock is coming. After a short time, just the beep (without the shock) causes the animals to freeze and, crucially, causes the production of endocannabinoids in the brain. The relevance of this model to the human condition is obvious. PTSD symptoms are often triggered by exposure to something in the environment that reminds the sufferer of trauma.

After a while, rodents, like most people, will learn that the beep no longer means that a shock is coming and will no longer freeze when the beep is played. If animals are treated with a drug that blocks CB1 receptors then they show a profound inability to forget. The same result is found in mice genetically engineered to not have CB1, playing the beep causes them to freeze long after normal animals have learned to forget. Again, the relevance to PTSD is obvious; only some people who experience an extreme trauma will develop PTSD. Could genetic differences in their endocannabinoid system help explain why this is?

Perhaps most interestingly, animals given an extra booster of endocannabinoids find it easier to forget. Drugs which inhibit the breakdown of endocannabinoids by blocking FAAH have the same effect, suggesting that medications which stimulate the endocannabinoid system may be beneficial in the treatment of PTSD.

Exposure therapy is a commonly used treatment for PTSD; patients are repeatedly re-exposed to those triggers which precipitate their symptoms, much like the rodents and the beep. This tactic is completely at odds with the intuitive response of PTSD sufferers, who will actively avoid these triggers. As I mentioned above, basic research findings indicate that exposure to these triggers causes the brain to produce it's own cannabinoids, which then help the brain to forget. Perhaps the brains of PTSD sufferers have impaired cannabinoid synthesis, or maybe they break it down more quickly. Thus maybe cannabis treatment would be the most effective when given during exposure therapy?

That's the basic science. Sounds simple right? In fact it should be a no-brainer that cannabis use will be beneficial for PTSD sufferers?

Well, as so often occurs in science, it's not that simple. A major problem is that the cannabinoid system is found in almost all part of the brain and as such is involved in many different biological processes. A sobering example of this is the weight loss drug Acomplia TM from Sanofi-Aventis. The rationale behind this drug is reasonable enough; smoking pot gives people "the munchies", suggesting endocannabinoids promote eating. Blocking the CB1 receptor (with AcompliaTM) should therefore reduce food intake. Sure enough, it does. But it also makes people depressed and has other psychiatric side effects. These side effects are so severe that AcompliaTM has been withdrawn.

Cannabis also has a lot of potential side effects, many of them undesirable; apathy, psychosis, respiratory problems associated with smoking, prenatal toxicity, addiction (although this is controversial). One of the most troubling side effects of cannabis is that high doses can, in some people, trigger bouts of extreme anxiety. Not something any PTSD sufferer would want.

Another problem is that THC, the major active ingredient of cannabis, is not the same as the endocannabinoids found normally in the brain (otherwise we'd all be high all the time). It's not entirely clear that THC has the same "memory-erasing" effects as the brains natural endocannabinoids. In fact some researchers even think that treatment with pure THC may have the opposite effects, delaying an animal's ability to forget.

Nevertheless, a holy grail of "medical marijuana" programs for cancer and pain is the design of drugs which have the beneficial effects of marijuana without these undesirable side effects. Drug design programs based upon this reasoning may themselves eventually have a very beneficial side effect; drugs which can help PTSD patients forget.

 

Philip M. Newton, Ph.D. is a Neuroscience Lecturer at Swansea University Medical School in the United Kingdom.

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