About stress and anxiety

Stress is a fascinating thing to study because like death, it’s inevitable. Everyone faces it in their day-to-day life. I study how stress affects the brain. Now, most of the stress that we face as regular people on a regular day-to-day basis is things like economic downturns, relationships ending, issues like this which are manageable, but they wear us down. So, what I’m going to talk about today is traumatic stress. This is a different beast.

What is traumatic stress?

Traumatic stress. This is going to encompass things that are much more severe. There’s kind of a gradient of how we look at stressful events in our life. Things that are on the traumatic side, this is gonna be something like a physical assault, a sexual assault, a car accident, a natural disaster like an earthquake, being in the middle of a war, for a lot of veterans who’ve been over there. Traumatic stress seems to have a different effect in terms of it can really leave a residual impact on someone.

What is PTSD?

Statistics seem to predict that roughly seven out of ten people or about 70% of the general population in North America will be exposed to some form of a traumatic stressor in their lifetime. That’s very interesting because that’s a pretty big subset of the population. But what’s interesting is that of this 7 out of 10, or 70%, only about 10% of these people will then go on to actually develop post-traumatic stress disorder, and what that equates to is that within the general population what we’re looking at is roughly 8% of the people in North America at some point in their life will experience post-traumatic stress disorder. There are a few questions that are very key, and the psychiatric research world is really interested in answering with respect to PTSD. One of these is, What’s so different in the brain of someone who has PTSD versus someone that doesn’t? And also, another important question is, why do some people develop PTSD and others don’t? I’d say we’re halfway there. I think we’ve got a pretty good idea about what’s going on in the brain. What we do not know is which people are vulnerable and which aren’t. There’s a lot of effort being directed into this to try and see if there is some kind of biological signal that we can extract from someone’s DNA, or from their blood, or some other measurement that will predict if they get sent to war and they experience traumatic stress and when they come home, do they have a good chance of getting PTSD? So that’s one of the things that we’re looking at trying to figure out.

What we’re really talking about today is, What happens in the brain when someone has PTSD? I’m going to give you a crash course under anatomy which I think is very relevant, and hopefully, you’ll get some tidbits you can take on your own with this.

The Amygdala and PTSD

I’m going to talk about a part of the brain called the Amygdala. You can see it up there. It’s actually the Latin word for almond because it is actually shaped like an almond. The Amygdala is an absolutely fascinating part of the brain. This is what assesses our environment. All our sensory information gets funneled in through our sensory cortex and gets processed. It gets dumped into the Amygdala where essentially valence is assigned, and the Amygdala then says, Is this something that’s good, is it safe, or is it bad, and is it scary? This decision is largely done through cross-talk between another part of the brain called the prefrontal cortex, and in humans, and all mammals, this sits at the front of the brain. But for us, this is really well developed. This is the part of the brain that allows us to engage in very complex forms of cognitive processes and thinking, like, let me evaluate decisions before I say something. This is the kind of brain that gets turned off when we drink a lot of alcohol, for example. People don’t quite think their way through things. So, it’s interesting in the context of stress and PTSD.

So, we have the Amygdala. This is the part of the brain that’s constantly bombarded with stimuli – good, bad, safe, dangerous. Now a lot of these decisions are made by the Amygdala talking to the prefrontal cortex, and it says, Have we seen this before? Is it safe or not? Essentially, what will happen is, if a stimulus is determined to be potentially threatening, the Amygdala essentially will activate a cascade of brain circuits that results in us feeling anxious. It causes the release of hormones like adrenaline and will push us into a stress state. What the prefrontal cortex does is that it tempers the Amygdala. So, I think the best analogy for this is: Picture a guy riding a carriage, and he’s got reins on the horse. In this situation, you can say the Amygdala is the horse, and the prefrontal cortex is the guy with the rein. What his job to do is to keep the reins tight and make sure that the horses don’t run wild. Essentially what happens if the prefrontal cortex isn’t online, or isn’t communicating with the Amygdala, is that the horses run wild. In this case of the Amygdala, what this means, is that it loses the ability to start referencing information appropriately and saying, Is it safe or not? What happens in that situation is that it seems to flip into this default mode which is, Okay, I’m going to assume everything is potentially dangerous, and I’m going to flip into the state of vigilance where our constant surveying of the environment is looking for threats in danger. At a low-grade version of this, you’ll get what we would call a worrywart, someone who always seems to find danger in the world. At the really extreme ends of this, we have something like PTSD.

What we’ve learned through neuroimaging studies in PTSD is that there is a very notable disconnection between these brain regions. What you can see here is the VMPFC, the ventromedial PFC. This is a really important part of humans and the Amygdala is in the lower panel. What you can see is basically a color map. Things that are blue mean that these parts of the brain are less active in individuals with PTSD than they are in healthy controls. Things that are yellow are more active in individuals with PTSD than they are in healthy controls. What this is telling us, and what a collection of studies from a large number of researchers around the world have told us, is that essentially what happens in PTSD is that we have hyperactivity of the Amygdala coupled to hypoactivity of the prefrontal cortex. Essentially, going back to the horse analogy, the guy in the carriage has just given up essentially, and let go. And the horses are running wild. What you get is the development of these states of anxiety, arousal, and stress that an individual with PTSD experiences.

As I said earlier, what we don’t understand is why some people develop PTSD and others don’t. This seems to be the kind of, let’s call it a signature of the brain pattern activities, that define PTSD. But we don’t know why it is that some people experience this so this leads into the question and the topic I’m going to go about today which is… What about cannabis?

Cannabis oil and PTSD

What about cannabis oil? There’s a fair amount of media attention in this regard. There have been a lot of people who have come out over the last few years, most notably the RCMP officer who is smoking marijuana in his outfit in his full RCMP garb, and then got caught and was explaining he was using it to regulate his PTSD. There’s a lot of blowback because people say there’s not enough evidence to look at this. This has led to the question that has really piqued a lot of people’s interest, which is, Can cannabis oil help? Certainly with PTSD, and in this case, Newsweek asked this question within the context of veterans.

What I’m going to do is explain to you what do we actually know about this, and is there any scientific basis to support these claims? What was really interesting is, through advances in neuroimaging, coupled to psychopharmacology, we can start looking at what the effects of drugs are on brain imaging patterns.

Studies on PTSD, anxiety, cannabis oil and THC

A group in Chicago did a series of very interesting studies. What they did is that they put people in a brain scanner. They had them look at images that we know light up the Amygdala since this is the part of our brain that searches for threats. It’s a threat detector. In our environments, it lights up very reliably with things like a picture of a weapon, a scarred face, blood, and a car accident. Things like this will reliably turn the Amygdala on. What they did in this study is that they gave people in advance THC. THC, for those who don’t know, is the psychoactive constituent of cannabis oil. This was an isolated preparation from cannabis to say, Well, what does THC do to the Amygdala when someone gets stressed out?

What they found was that they actually got a very robust blunting of the Amygdala in response to stress cues. You show people these things that normally light up the Amygdala and help generate a state of anxiety and in the presence of THC, this just didn’t really seem to happen. What we’ve learned from animal research to add on top of this is that cannabinoids like THC actually seem to have the ability to reduce the fire-activity of neurons in the Amygdala. The way that they seem to do this is they seem to be able to inhibit the release of excitatory neurons in the Amygdala.

There are two kinds of neuro-chemicals that we have – essentially excitable ones, that when they get released they make neurons fire and brain areas light up, or inhibitory, and when they get released they silenced neurons, they quiet brain areas down. In the Amygdala, the release of excitatory neurochemicals is known to activate this part of the brain in response to stress, and this helps to generate that state of anxiety. What we’ve learned from the animal side of things, building off of what we’ve learned from humans, is that, yes it looks like in humans you can decrease activity in the Amygdala. From animal work we’ve learned that you can actually quiet down the activity of those neurons. So, there does seem to be some interesting evidence there. But what about the other side of the coin which is the prefrontal cortex? This is what I find fascinating about the effects of cannabinoids is that they’re very brain region-specific. They don’t just do the same thing everywhere in the brain.

Another group, this is really interesting, studies where they were training people to learn to associate two things together that are aversive. In this situation, you would play an auditory tone and then they give people a mild electrical shock. You do these enough and then when you play the tone, people actually start sweating. You get a skin-conductance-response because they’re expecting that they’re going to start getting a shock delivered to them. Then what they do is they just start playing the tone without getting a shock. What we are able to do as organisms that have the abilities of complex cognitive processes is that we can unlearn that, in a way. We can extinguish that memory. Doing this seems to really involve the prefrontal cortex. During these tasks, the prefrontal cortex comes online and it’s essentially is telling the Amygdala, No, don’t worry about it anymore. This isn’t predictive of danger. In this study, they did that task, but it’s similar to the last one. They either gave them THC in advance or didn’t. They saw what happened. What was interesting was, first off, giving people THC really facilitated the ability to now learn that that was no longer a danger signal, so, promoted what we would refer to as this fear extinction or safety learning. At the same time, when they looked at the neuroimaging patterns, like the previous study, they did see reduced activity in the Amygdala. But interestingly, they actually found increased activity in the prefrontal cortex. What this is saying is that you’re getting very different effects of cannabis in two different brain regions. Again, we can lean on the animal work that we’ve done to try and understand this. One of the things that we’ve learned from animal research is that unlike what happens in the Amygdala, in the prefrontal cortex we can actually see that cannabinoids like THC turn off those inhibitory neurons. They suppress the release of inhibition. By doing so, they take the breaks away so that the system becomes more active. What you’re really ending up seeing here is this pattern of neural activity where PTSD is characterized by a hyperactive Amygdala that’s just gone wild on its own and a deficient prefrontal cortex. Then, what we see with cannabis is actually the exact opposite neural signature where we get blunted Amygdala activity and more activity in the prefrontal cortex. Tying this into, What does this mean for PTSD?

What’s very interesting was that clinical trials looking at cannabis are decidedly unavailable. There are just not many of them. It’s been something that has fueled the debate between the advocacy crowd and the legal crowd for quite a few decades. One of the things that have actually been done that do provide us with some information is that you can get doctors to prescribe pharmaceutical-grade THC, and this is referred to as Nabilone. A study was actually done in Canada in the Canadian military. A psychiatrist had a bunch of military personnel who had developed PTSD. They had pretty severe PTSD. They had gone through several different pharmacotherapeutic agents. None of them worked. So, they’ve gone through several drugs and they were still having really violent nightmares that were very intrusive. Hyper aroused, anxious, not very functional on a day-to-day basis. They gave them Nabalone before they went to bed. Either Nabalone or placebo. It was a completely blind trial, of which there are few in this field. Basically, what they found was that individuals who got Nabalone or synthetic THC before they went to bed stopped having nightmares almost immediately. The nightmares curtailed quite a lot. What they found was this trickle-down effect where the individuals then started having these really big increases in their well-being scores. When the psychiatrist would ask them on a day-to-day basis, Are you doing better?, 9 out of the 10 people who went on Nabalone said, Yes we’re doing better. 0 Of the 10 people who were on placebo said they had any change. This was within subject groups that they actually swapped. These were the same people who without knowing which drug they were on had very notable differences. That’s actually the first bit of, I would say, true clinical evidence that there is some signal here. That’s actually quite interesting.

Does cannabis oil help people with PTSD and anxiety?

Let’s go back to that Newsweek question then which is, Does cannabis oil actually help people with PTSD? The answer I would have to say, at this point is, maybe, with signs pointing to probably, and that will bake the next question which is, Does that mean that smoking pot is a good cure for PTSD? I would say probably not. This is not something that’s like a general approach. I think that should be taken in medicine it’s telling us something, and there are people who have through self-medication learned that it helps their symptoms, and that’s good for them. But in terms of using this as a new medication approach, there’s going to be a lot of issues surrounding that, and given that there’s a lot of change in the legal landscape in Canada, that may be coming in the next couple years and it will be very interesting to see where this goes.

The one thing I’m really hoping for is more actual clinical trials so that we can answer that question definitively, yes or no. Thank you for your attention.

Questions for Matt

You’re asking, Are the neural activity patterns the same in someone who has PTSD the same as someone who doesn’t? Those studies have also not been done. Almost everything that’s been done with THC in these neuroimaging studies is all done in healthy controls. There is a recent beginning – the pharmaceutical companies are getting interested in this, not from a marijuana perspective, but from the brain makes its own version of marijuana (perspective). It’s like an endorphin. Everyone knows what endorphins are, but there are also these things called endocannabinoids. It’s like the brain’s version of THC. That’s the therapeutic target that they’re trying to take. Now, is to say instead of giving THC, let’s see if we can just boost the brain’s version of THC and this is the research we do. There are studies ongoing now with that to see if you can boost the brain’s version of THC and if that has a similar effect on neural activity patterns in someone with PTSD and someone that doesn’t. More importantly, they want to see if boosting the brains natural THC will change the brain of someone who has PTSD to look more like someone who doesn’t. Can you get the prefrontal cortex and the Amygdala talking again? Can you reinstate that communication in the circuits that seem to have uncoupled? Okay, yes, it’s possible, it’s definitely possible so repeat.

Can you drive a car while taking cannabis oil?

The question was, with respect to driving a car? Driving a car requires a certain degree of vigilance. Is THC affecting these the same way? What has actually come out of the simulated driving studies with THC is it’s interesting because it’s different than alcohol. What seems to happen with alcohol is people don’t realize that they’re as impaired as they are and they drive excessively fast. People under the influence of THC seem to be hyper-aware of the fact that they’re inebriated and they end up driving excessively slowly. What ends up happening during these driving studies that they’ve done is the reaction time seems to be a bit slower when they’ve simulated a child to run in front of the car, or something. But the actual incident, accident rate, is almost exactly the same because there’s this kind of compensation that they develop. That being said, it’s been very hard to tease out. This has been the big question on the legal landscape. How do you create a cannabis breathalyzer? There’s going to be some degree of impairment that comes from it, but it’s not like alcohol. The metabolism is so different that you really can’t accurately tell within 24 hours when someone has consumed. It makes that very difficult from a legal standpoint. The evidence would suggest that, yes, there is some degree of impairment. But there’s this interesting compensation that you don’t see with alcohol.

I haven’t run any of these studies. I’m a basic scientist who’s primarily doing animal stuff. I’ve read the studies and I’ve talked to a lot of people that do these things. What’s interesting is in the general public with THC, in cannabis oil, there is a reasonable proportion of people that have very adverse responses where they develop intense states of panic and paranoia. I have not actually seen that ever reported in any of the studies where they’ve worked with highly anxious populations. There was a group of studies that came out a couple of decades ago that looked at social anxiety and generalized anxiety and now there are PTSD studies coming out. In all of these studies, there seems to be actually a reduction in the meaning of that. No one really understands why you’re not seeing the same proportion of adverse responses. You do get some adverse responses. People do tend to say, Yes, you know, my short-term memory is a little compromised. I get kind of tired a lot more. I might eat a lot more. I guess those are the kind of standard side effects that you’d see.

Will there be more cannabis oil research?

The question is, are there actually any studies going forward looking at cannabis oil in PTSD? As far as I know, yes, because one of the things that are occurring in the Canadian landscape is with the new medical designation of cannabis, the way that health Canada has redefined it, what they actually want now is these licensed producers to have clinical data to be able to back up any claims they make. A lot of these companies are trying to find medical collaborators to which they will help fund studies to look at this. One of the primary indications in PTSD as per the comment you had about the people, the benefit seems to be in those that are actively going through other forms of treatment as opposed to people who are just using cannabis oil. That does not surprise me because all the studies that have been done where they do this kind of unlearning of fear, essentially it’s when you couple cannabis oil with that process. It enhances the brain’s ability to take that new learning. All the studies that I’m aware of, because of the ethical setup that you do in medicine, you can’t nowadays deprive people of some form of treatment in the psychiatric sense, from what I’m aware of. Everyone in these studies all get some form of CBT, so they’re all getting some form of therapy. On top of it, they’re adding placebo or THC to the mix. This isn’t like what you’re saying where people are, I’m assuming, just kind of lying on a couch smoking pot and they’re like, I don’t get any better. I guess that’s not hugely surprising because you do need to couple it. This is an argument in biological psychiatry that we’ve made quite a bit. With a lot of the medications that we get, is just handing it to someone doing anything or do you need… is really what these drugs are doing is that the windows of plasticity in the brain that will take the new learning better. And I agree.