In the last post, we looked at some of the areas in the brain where stress reactions occur, and their interactions during a typical acute stress reaction. Now, we examine disordered stress, and the changes reflected in brain signaling.

What are the disorders of stress response?

Acute Stress Disorder (ASD):

An acute (2 days – 4 weeks) experience of the below symptoms, within a month of experiencing a severe trauma (defined as a situation where one witnessed or experienced something very distressing, a loss of control over traumatic circumstances, the possibility of losing one’s life, and similar.)

Post-traumatic Stress Disorder (PTSD):

A more chronic, lasting experience of those symptoms compared to ASD.

Generalized categories of symptoms:

Intrusive memories

Avoidance of related memory triggers, general numbing of feelings

Hyperarousal (increased vigilance of surroundings, for example)

Symptoms disrupt normal day-to-day function

**A note: this is not intended to be medical advice, nor should it be taken as such. If you are concerned about any medical condition you think you may have, please contact your doctor for professional advice.

Many of us start to think of military veterans coming home from conflicts overseas when the topic of PTSD comes up. Indeed, that is a serious issue facing returning soldiers coming back to their lives at home and it deserves every ounce of the attention it gets. But I also want to take a moment to point out that PTSD is not just for people who have seen combat. Roughly 7% of the general US population lives with PTSD, which can arise from car accidents, incidents of violence, childhood abuse, and many other experiences one can have without even leaving one’s hometown. So this is something that could potentially affect anyone.

Adaptations in the brain

As I've probably mentioned more than enough times, stress disorders represent an adaptation to survive a tremendously stressful situation, without the re-adaptation back to a usual level of stress reactivity afterward. The result is a continued stress response even after the context/reason for stress has ended. Recall that we’re talking about 3 major brain areas that interact during a stress response, but also that these are not the ONLY brain areas that are involved.

We have the amygdala (the fear/emotion responder), the hippocampus (event memory), and the prefrontal cortex (behavioral control) interacting to produce a response to aid in avoiding/escaping a harmful situation. Normally, these three areas work together to help you get out of a bad situation and then resume normal function. But this isn’t always the case. Sometimes the brain over-responds and doesn’t adapt back to typical function so easily.

Normally, we have this nice little response as diagrammed below. The amygdala responds to fearful/emotional cues in the environment, and that triggers some strongly encoded memories of the event in the hippocampus. The hippocampus and amygdala responses to stress dampen the behavioral inhibition from the prefrontal cortex. Hopefully very soon thereafter, you've escaped from whatever stressor was threatening you, and usual function resumes.

But in ASD or PTSD, the brain’s adaptation to the environment doesn’t resume usual function, and the result is that fear/emotion area has adapted to be especially responsive. Meanwhile, the other two arms of the circuit are weakened. The representative balance between the three brain regions we're looking at here changes to this:

Where the amygdala is less inhibited and fires more, it alters the timing of neurons firing in the hippocampus, which makes for weaker encoding of new memories and weaker inputs to the PFC.  The reduced inhibition from the PFC lets the amygdala continue firing more, which relays to the hippocampus, and further reduces the inhibitory signal coming from the PFC. The checks and balances between the three regions are weakened substantially. At this point, reminders of the event trigger an inordinately strong emotional reaction in this signaling pathway, while "un-learning" or extinction learning is weakened. This reaction results in some of the symptoms of stress disorders- a reminder triggering the sense of re-living the event, for instance. Of course, there are other brain areas contributing here, and I don't want to discount them. But this is a pretty substantial shift of normal signaling!

But just because a signaling pathway in the brain is adapted to work differently from normal doesn't mean it is permanent. There are some treatments available now and others coming up that might provide help and support for people who are dealing with ASD or PTSD. We'll take a look at some of those next time.

[second in a two-part repost series for your reading pleasure! -leigh]

Continuing my discussion of the purported “legal marijuana” from my previous post, for this post I’ll move to the topic that’s probably of greater interest: what do these drugs actually do, and what’s different about them?

I already covered that JWH-018 is a synthetic compound that is structurally unrelated to THC, the principal psychotropic component of marijuana. I also mentioned, but not in great detail, that it works via the same receptors as THC does, and that it and some other compounds from its family of structures (the aminoalkylindoles) produce cannabimimetic (cannabis-mimicking) effects.

Cannabimimetic effects encompass several different physiologic changes. In rodent models, a “tetrad” of effects (catalepsy, decreased locomotion, hypothermia, and hypoalgesia) are measured as the benchmark of cannabimimetic effects. Of course, rodents aren’t so good at telling us when they’re experiencing particular psychedelic effects, so we can’t measure that specifically. In humans, perceptual alterations, memory alterations, and euphoria are commonly discussed cannabimimetic effects.

That brings us to the big question:

If these drugs produce similar effects and work via the same mechanism, how can they be different?

Oh, there are many ways.

Let’s consider some of the most basic pharmacological properties of any given drug. The drug has to bind to its target, it has to cause an action at that target- and if it’s psychotropic, it has to get across the blood-brain barrier to do any of this. Only then are the effects of the drug actually set into motion.

Before it can cause an effect, the drug molecule needs to run into and bind to its target. This very first step carries a lot of variability across different drugs, even at the same target. Seemingly small changes in chemical structure of a drug can have a dramatic impact upon how well that drug will bind to its target. In this case, the target is the cannabinoid CB1 receptor, which is expressed widely throughout the brain and mediates the psychotropic effects of THC. Since living systems add a big pile of other variables we won’t get to just yet, pharmacologists typically measure this basic property of drug-target affinity in vitro. If a drug will bind easily to the receptor even at very low drug concentrations (very low doses), that constitutes very good affinity. Potency is a closely related measure, where the dose that causes a physiologic effect in a system is measured.

Figure 1. Drug potency as shown in typical dose-response format. A drug that produces an effect at a lower concentration is considered to be more potent. Lower potency drugs have curves that are shifted to the right, meaning that more drug is required before physiologic effects can be measured.

The few studies that have looked at the pharmacology of JWH-018 at the CB1 receptor have shown that JWH-018 is more potent than THC. It will bind the CB1 receptor at considerably lower concentrations than THC will, and lower doses of JWH-018 are required to produce physiological responses.

Next is the specifics of the drug action on its target. Most drug targets don’t function as all-on or all-off, like a light switch. Instead, consider them more like a dimmer switch. Different drugs (again due to their differences in chemical structure) can cause different levels of activation of the target. This is the efficacy of a given drug at a given target.

Figure 2. Drug efficacy, again in typical dose-response format. Drugs with high efficacy produce a greater maximal effect than low-efficacy drugs. These curves can also vary by effect for drugs that produce multiple measurable effects. There are places in medicine, for example, where full agonists are the preferred tool to use, and places where a partial agonist is better. It all depends on the conditions! More effect is not always better.

A drug that activates the receptor is generally known as an agonist. But since there are varying levels of activation that a given drug can cause at a receptor, we sort the agonists into categories. There are partial agonists, that don’t activate the full capacity of the target, and full agonists, that do. THC is a partial agonist at the CB1 receptor, only partially activating it. On the other hand, JWH-018 is a full agonist. This is a major difference in and of itself- CB1 receptor responses, and immediate and long-term cellular adaptations in response to drug, vary with different agonist efficacy. The particular psychotropic effects of THC are distinctly related to its partial agonist nature. This does not mean that JWH-018 will make users “more high” than THC or is somehow “better” than THC – just that the immediate and long-term effects are distinct and can’t be described as “the same thing but more powerful.” If you take one thing away from this post, let it be that.

Recall that living systems add a whole lot of complexity on top of the already fairly complex drug-target interactions that I’ve discussed so far. Let’s consider how the drug gets to the receptor in the first place. Drugs have varying absorption and distribution kinetics, which can also modify the drug effect. Something that gets into the brain very slowly will give a different effect than something that reaches the brain rapidly. We know essentially nothing about the absorption and distribution kinetics of JWH-018, it’s all up to speculation.

Speaking of kinetics, metabolism/elimination kinetics are also quite variable between different drugs. And on that hand, we’re in the same position as with the absorption and distribution kinetics. No solid understanding. Some clever folks are developing methods to detect metabolites of JWH-018, but that’s where we are.

So to summarize:

1. JWH-018 is more potent than THC. Lower concentrations of drug will produce notable effects with JWH-018 than with THC.

2. JWH-018 is more efficacious than THC. The maximal effect of JWH-018 is greater than that of THC in every physiological measure that’s been captured to date.

3. The points I bring up in 1 and 2 DO NOT mean that JWH-018 is like THC, but “better” or “stronger” or any other comparator. The considerably different pharmacological properties of these two drugs causes them to have (perhaps related but) distinct effect profiles.

4. We have little to no scientific information about how JWH-018 is distributed and eliminated from the body.

5. We have little to no scientific information about JWH-018 beyond what I’ve outlined here.

Alright, we can talk theoretical concepts and isolated measured properties of drugs all day, but the bottom line is that people are trying this stuff out and perhaps using it regularly. How do the limited data we have translate to people? Unfortunately, there’s not a ton of properly-controlled study of the stuff in model organisms, much less humans. So we know very little except what we can speculate from the basic pharmacology that we do know about.

Not surprisingly, there are plenty of people willing to venture out and be their own n=1 case study, but the information we can gain from those people is pretty constrained. Is this a call for more study? Perhaps…

[another repost in a 2-part series, but this time because the topic is very much in demand lately. -leigh]

I’ve been noticing lots of talk of these “new” synthetic cannabinoids floating around out there lately, now that Spice and K2 have gotten a lot of media coverage. I also found a lot of hearsay and uninformed opinion floating around on the internet in various places, but not so much of the scientific information. Let’s remedy that, shall we? I’ll cover the basics over a couple of posts and more if there are remaining questions.

Spice and K2 are being floated as the new “legal marijuana” – a supposedly marijuana-like high without legal consequences. Abel Pharmboy kicked off the discussion with a Research Blogging post about synthetic cannabinoids that you should definitely check out. DrugMonkey brought up an interesting thought in his post on the topic: does the US Controlled Substance Analogue Enforcement Act of 1986 apply? This act states (I paraphrase here) that a compound that shares a similar chemical structure or pharmacological action and is intended for human consumption is treated as a Schedule I classified drug. According to some interpretations of people who know more about legal stuff than I do, that might be a negative. So let’s explore the chemistry of the cannabinoid agonists** to get started.

**Disclaimer: I am not an organic chemist. Don’t crucify me.

Delta-9 THC, the principal psychotropic ingredient in marijuana, is a terpenoid compound produced by the Cannabis sativa plant. You can examine its structure here:

Figure 1. THC chemical structure (via Pubchem)

THC acts through brain cannabinoid receptors to produce its typical effects. However, those receptors are involved in a whole lot more than just producing the psychotropic effects of cannabis intoxication. The pursuit of understanding the mechanism of action of cannabinoids, as well as further research to better understand the normal and abnormal physiology of the endogenous cannabinoid signaling system, has resulted in many novel synthetic drugs designed to target the cannabinoid receptors in experimental systems. They were devised to be used as tools to elucidate what happens when we probe the system- for instance, what molecular properties are required for a given drug-receptor interaction property (efficacy, affinity, what have you).

There are multiple classes of structurally distinct cannabinoid agonist drugs that emerged from these efforts. Given the topic under discussion here, I will focus on the aminoalkylindoles. They are structurally unrelated to delta-9 THC, as you can gather by the structure.

Figure 2. Aminoalkylindole cannabinoid agonist WIN55,212-2 structure (also via Pubchem)

Here’s where I bring in the so-called “legal marijuana” – one of the compounds that’s causing this stir, named JWH-018, is a derivative of the aminoalkylindole class of drugs. Take a look for yourself, and consider the similarities to the aminoalkylindole above.

Figure 3. JWH-018 structure. Rotated (imperfectly, but you get the idea) to demonstrate structural similarity to figure 2.  Pubchem may be a good start, but how about we get something that lets us rotate around bonds? Get on that, NCBI.

Note again that these are synthetic compounds- they are not analogs of THC and not produced by the Cannabis sativa plant. They are structurally unrelated, but act upon the same receptor as does THC. They have different pharmacological properties: efficacy and potency, which I will discuss in the next post. This does not make them “better” in some or any way compared to the plant-derived cannabinoid compound.

Now the curious thing is that while these synthetic classes of compounds may be structurally distinct from the original cannabinoid compound of interest, they do produce pharmacological effects that are classified as cannabimimetic. And yet, one does not need a DEA license to obtain some of these research chemicals.

Many of these “legal” products are distributed as plant matter soaked in JWH-018 and other compounds, and then marketed as incenses- covered with warnings about how they are not intended for human consumption. This is also curious. How long will this hold off the inevitable? I don’t have a guess.