Thanks to everyone who contributed and commented on the relocations poll! I thought I'd graph up the data and share the responses.

There were n=48 respondents to the poll, and everyone answered both questions. Unfortunately, Polldaddy doesn't give me correlative results, so I don't have info for number of relocations broken down specifically by career stage. But it's something.

First question: How many relocations have you made for career or training reasons?

Figure 1. Number of relocations

Next question: what career stage are you in?

Figure 2. Current career positions

Looks as though most respondents fell into the 2-4 relocations range. However, there are a number of responses indicating more than 4 moves, including at least one "extraordinary" number. (Yikes!) Science is a demanding career, indeed. I wish I had asked how many of those moves were paid out of pocket vs reimbursed! On second thought, the results would probably be depressing.

The most common responses for career stage were 1st Postdoc and 1st Permanent position. (I'm not sure whether the prevalence of 2nd+ Postdoc should be disheartening, or encouraging in that "misery loves company" kind of way.) While we can't correlate due to the data limitations of polldaddy's free accounts, I think it follows the typical career track well to speculate that the 2-4 relocations range is likely associated with these career stages.

One thing I particularly liked is that people from many different places contributed to the poll. There were 12 countries represented among the responses! Awesome! It's always a plus to get a more well-rounded perspective on careers, as well as to see that my readers are not totally US-centric.

These results also let me feel a little more "normal" - at a time when basically my entire family is asking when I'm going to get a job closer to home (i.e. them) and quit my gallivanting around the country, this is particularly helpful.

I was pondering the number of major relocations I've made (and consequently, dragged spousal unit through as well) in the name of my scientific training and career development.

There was the first one, to go to college as far away from my hometown as physically possible without losing the in-state tuition benefit. (ok, there was more reason than this, and I adored my college years, but that was a damn compelling reason to start.)

Then a pretty big cross-country move to go to MegaU for grad school.

Next, another substantial relocation for my first postdoc position.

Finally, another long haul to wind up in my current position. I'm hoping we can settle down here for a while now. Though let me tell you, after all that, we are some experts when it comes to downsizing, packing, and methods for transporting goods and pets.

All this has me wondering. How many moves have YOU made for career- or training-related reasons?

And since my follow-up thoughts are more discussion and less surveyable, feel free to leave a comment about the following:
Was it exciting and enriching to see and do something new, or was it just a pain in the ass? Were spousal career issues affected? To what extent did this influence your career path?

Am I *ever* grateful for locally administered corticosteroids and local anesthetics right now.

I owe that to the many who have walked this way before me.

/just another day in the life

This is supposed to be the *twelve* months of Neurodynamics post, per the meme that's being passed around the blogs. I haven't been running this joint long enough to have twelve months of archives yet, so how about an abbreviated version?

August Welcome to the Neurodynamics blog! I’m Leigh, and I’ll be your tour guide.

September Last time, we got started with a discussion of stress reactions and brain adaptations.

October I've briefly mentioned the BBB and other extra barriers to drug permeability in a post about pharmacokinetics.

November This is one I have seen rising among my blog search term hits.

December Reader Abbe commented with a question about drug common pathways and interactions.

Reader Abbe commented with a question about drug common pathways and interactions.

In the book, The Science of Marijuana, Leslie L. Iversen, 2008, p. 56-57:
“Experiments with nerve cells in tissue culture or with thin slices of brain tissue incubated in the test tube have shown that the addition of THC or other cannabinoids can inhibit the stimulation-evoked release of various neurotransmitters, including the inhibitory amino acid GABA and the amines noradrenaline and acetycholine (Szabo and Schlicker, 2005).”

I have a question about GABA, the inhibitory neurotransmitter and cannabis. If I understand this correctly, cannabis inhibits GABA release. Less GABA in the system causes a whole raft of problems: increased muscle tension, anxiety, problems with sleep, and more.

I came off ten years of Ambien use for sleep issues. It was a living hell getting off this stuff. Ambien works on the same receptors as the benzodiazepines and artifically ups GABA in the body, which causes the body to stop producing so much GABA. Go off the stuff and you get serious withdrawals, and it can be life-threatening for some people. Their is a seizure risk when going of these drugs, tapering slowly is key to let the body start making more GABA.

Four months ago, I was given a medical marijuana recommendation by one of my doctors. I live in a medical marijuana state. So I started using cannabis for chronic myofascial pain. It worked great for a while, but now my myofascial pain has returned with a vengeance. I wonder if it’s because of cannabis’s effects on my GABA levels.

If cannabis is suppressing my GABA levels, I’m back where I was in the Ambien withdrawal cycle.

Any thoughts or comments?

Yes, Abbe! I have many thoughts and comments! I think we should start by looking at mechanisms of the drugs mentioned.

Abbe posted the question on my Pharmacology of Marijuana post, where I wrote that THC actions at CB1 receptors resulted in the suppression of neurotransmitter release at the presynaptic cell. This applies to GABA release in addition to several other neurotransmitters, just as Abbe quoted from the book she had read, so she is exactly right.

In the course of thinking about this question, I realized that I haven't written a post specifically on sleep drugs! Well, damnit. That's a very nice topic for a full drug mechanisms post. But since I'm answering a question here, I will keep it brief. Ambien, aka zolpidem, belongs to the sedative-hypnotics class of drugs. What this class of drugs does is dose-dependently reduce consciousness. In the case of the sleep drugs, this is accomplished by selectively enhancing the effects of GABA signaling at the GABA(A) receptor, a mechanism we call positive allosteric modulation. They do not act as agonists all on their own, the presence of GABA is required.

Like many other drugs, tolerance does develop after repeated use of zolpidem. Withdrawal can be a difficult thing to endure, especially if it is after such a long term treatment as Abbe describes. In response to the enhanced effects of GABA, GABA(A) receptors can desensitize and downregulate, just as I've discussed in previous tolerance posts. Upon removal of the allosteric modulator, this can lead to a more excitable state in the brain, as the cellular response to inhibitory signal is desensitized. Tapering the dose of drug down helps to allow the receptors to slowly re-equilibrate and re-establish signaling sensitivity before the drug is fully withdrawn from the system.

There is a component of zolpidem tolerance that results in a decrease in extracellular GABA presence in some brain regions. This is likely due to a feedback regulation mechanism- more homeostasis at work. Again, a taper-off withdrawal from a drug would do exactly as Abbe indicates- allow the system to re-equilibrate slowly rather than shocking it all at once, which can have nasty consequences when GABA modulation is involved.

Now, back to cannabis and GABA, and to consider this common link.

While having THC on board and acting in the brain does reduce GABA release from the subset of pre-synaptic terminals that do contain CB1 receptors, this is not nearly as universal of an effect as something that targets GABA receptors. To make this more clear, yes, there are a LOT of CB1 receptors, and they are spread around many parts of the brain. But not all GABA terminals contain CB1 receptors, and not every instance of GABA release is suppressed by THC. This is in contrast to the situation with sleep drugs that target GABA(A) receptors, which are pretty much universally present at GABA synapses.

So I don't think Abbe is experiencing the same phenomenon with her medical marijuana prescription as she experienced with the sleep drugs. While  related, they appear to me to be distinct pharmacological and homeostatic phenomena. Though with some particularly interesting links, and I really am impressed by Abbe's critical thinking and putting that together.

However. This leaves a big question mark as to why her pain returned so voraciously. Why might that be? Well, there are many, many possibilities, most related to the fact that we don't know nearly enough about pain. (Pain Research Matters!) However, one thing that immediately came to mind for me, as I speculated what might be going on, was the observation that sometimes marijuana can cause an increased sensitivity to pain.

I know- stop the presses. (1) Marijuana is not all good?! and (2) Unexpected effects of a prescribed regimen?!

The sarcasm is not meant in any way to deride Abbe or the unfortunate increase in pain she is experiencing- I principally wish to emphasize that we find the unexpected in everything. Everything.

Snark aside, I'm really serious here. First and foremost, tolerance happens. After four months, depending on the regimen used, there could be receptor-level adaptations in the pathways that mediate pain, resulting in a pain increase and inability of the marijuana dose to overcome that pain signaling regulation. Certainly possible, and there are lots of individual differences here. But let's branch away from the homeostasis stuff here. There are two studies that I thought of when considering an increase in pain during marijuana exposure. First one points to a possible dose effect, with low doses reducing pain and higher ones having the opposite effect. THC has shown to produce biphasic effects in anxiety, for one- low doses typically produce a reduction, high doses an increase. It's possible this is part of the story. The next observation describes a potential mechanism for cannabinoid-driven pain sensitization. While a fascinating paper, even I find it a bit heavy to digest and would like to see further experiments. (When folks write for the glamorous journals, they have little space and lots of data. This usually annoys me and does not usually reduce the amount of time it takes me to understand wtf they did!)

Obviously, the clinical data we have to work with come with their own set of limitations, and a given individual's case might not reflect any one distinct observation we have available to us. In short, we know precious little about the instances and mechanisms of increased pain during marijuana use, but we have a couple of footholds and hopefully roads toward a better understanding. I suspect it's the combined effect of THC upon a diverse set of synapses, perhaps the dose regimen or term of use, and probably some differential tolerance (by type of synapse or by brain region or something else I haven't thought of yet). But that's just my wild speculation at this point, as we have no solid data.

Abbe, I thank you for what is probably the most fascinating reader question I've encountered so far. I hope I've been able to give you some more to think on as you move forward. I wish you the best of luck!

One of my favorite holidays is Thanksgiving. It's a nice time of year, the leaves are all crunchy, the air is crisp, it's cozy inside, I like turkey and all the fixings, all of it.

It's good for the mind to sit back now and then, and think of all the good things in life that you are thankful to have. Sometimes it can bring you out of a down spell.

Recently, as I was sailing through some troubled waters in my career, I had occasion to see in a very real way all that I had to be thankful for. I asked for help and support, and I got it in far more ways than I can imagine, from far more sources than I expected. People stepped up for me in many ways, from writing blush-worthy recommendation letters to reminding me that I was not insane. And all of it mattered.

That also sent me back to thinking of how fortunate I've been to have stumbled upon the people who influenced my life so positively. My life has been this non-deliberate, entirely haphazard path starting at 'bad news' and leading to my current stage. (which, well, at least it isn't 'bad news' anymore.) I'm very glad to have run into people who helped me to become better at the things I wanted to do and shared their successes and failures with me. The series of mentors I've found have changed my life, and probably in some instances kept me on the right path.

I am thankful for it all.

There are plenty of things to be thankful for in all aspects of my life. Being surrounded by good people is way up there on the list.

Leigh is moving up from being the data hunter-gatherer. This is not so easy. I've seen a ton of firsts in the last few months, enough to make my head spin. Certainly nothing my to-date training had prepared me for. And it leaves me exhausted.

So when I finally cleared the last hurdle today, last memo in hand, last signature collected, I kicked back in my desk chair and thought, "Ahhh! Now that's out of the way, I can get to the real work! The science!" (And then wished I could take a nap.)

But that is not really true. It's been pointed out to me, by people more wise and experienced than I, that I should be thinking of this differently.

It's all "real" work. For how many years, my job was to have someone else be administrator while I designed, ran, analyzed, and interpreted the experiments. With guidance, of course, because I was learning the job. Now my job description includes the facilitating science part. And it doesn't take long at this stage to see that without the work to facilitate the science, there would be no way to do the science. This all requires me taking a wider view of the process as a whole, and realizing that not all work in science involves running sample sets.

It's not an immediate change in thinking. I keep slipping back to "but where are the data?!!"

So I'm going to try this line of thought instead:

I've been working this strange and unfamiliar uphill battle for months, and learned a lot. Now I am glad that I can do some exciting stuff in the lab, because I made it happen. (And I needed a break from the administrative side.) Eventually, I'll publish it all too. With any luck, all this work will enable me to do more of the administrative shit, to do more of the benchmonkey shit, and more of the publication shit. It's all part of the science full-circle.

Now if only I can keep this in mind for next time. Because next time already looms over me.

I wanted a challenge- oh, I got it. I wanted to move up to the next step- and there are growing pains.

As I've posted before, we know pretty damn little when it comes to the spice cannabinoids like JWH-018. Particularly in humans. And this applies especially when it comes to interactions with the natural product cannabinoid we usually hear about, THC. Given that many spice users are former marijuana users, there are of course plenty of questions to be pondered when it comes to interactions.

And yes, I use the word pondered, because we have no data. None. Just so that's clear.

Many folks are using spice cannabinoids because of their legal status and because they fly under the radar on a urinalysis. That is, standard drug tests do not include a test for JWH metabolites, while they most certainly do for THC. This has ramifications for employment reasons among others.

So imagine someone switches to spice in order to continue their recreational drug use under the radar, so to speak. What effects would switching to spice have on getting rid of the THC in order to pass a urinalysis?

Short answer? Nobody knows a thing about this.

Long answer? I can provide some informed speculation, which is the best I've got.

First, on THC metabolism.

THC is a very hydrophobic molecule. In functional terms, this means that it would much prefer to hang out in the body fat tissue rather than the water-based bloodstream. And as it circulates around the body via the bloodstream, it will pass into the fat tissue or go through metabolism in the liver. (Catch up on the basics of pharmacokinetics here and here.) The THC that equilibrates into the fat will slowly return to the bloodstream over time, due to the concentration gradient effect. Because the concentration of THC is low in the bloodstream relative to the fat, the THC will move from the fat to the bloodstream.

It can take several weeks for a moderate user to clear the THC stored up in the body fat. Only when the THC returns to the bloodstream can it be taken to the liver and metabolized. This is why it can take several weeks between the time someone last uses THC and the time they can pass a drug screen.

Next, on how the synthetic spice compounds could affect this process

My initial impression was to think that there would not be a tremendous effect of using spice cannabinoids on getting rid of the THC, once a user has switched. The major rate-limiting step in THC elimination is that equilibration between fat and bloodstream. This is something that spice would not affect much without other factors getting involved.

But I could be wrong. If the synthetic cannabinoids and THC are all broken down by the same liver metabolic enzymes, it is entirely possible that the metabolic step could be slowed. By competing for the binding site of the enzyme, the spice molecules would reduce the rate of metabolism of THC. This would slow the diffusion of THC from the fat to the bloodstream, thereby slowing the entire process of eliminating the THC altogether. (Think of the number of cars in rush hour traffic competing for highway lanes vs the number at midnight- what's the effect? Everything is backed up.)

And if that's the case, it just might be that using spice to pass a urine test while still getting the recreational drug use on might be a double-edged sword. We have no idea.

This is one I have seen rising among my blog search term hits. A lot of my traffic comes to the recreational substances posts, and I view the search terms that landed readers on those posts as questions that are out there waiting to be answered. People are asking: can you get tolerant to marijuana by smoking spice cannabinoids?

The blunt and brief answer is yes. But let's discuss what cross tolerance is about. I'll be using the cannabinoids as my example, to keep the context in place. Also, because the cannabinoid signaling system is pretty interesting and unconventional. I like unconventional.

Cannabinoid agonists work their psychotropic effects by targeting the CB1 cannabinoid receptor in the brain. While different molecular structures will activate the receptor in slightly different ways, the general effect is that neurotransmitter release is inhibited in the presynaptic cell. (And this bit is why I had reposted my cannabinoid pharmacology oldie-but-goodie.)

But when you repeatedly target that receptor in the same way, what happens? Tolerance! There are several mechanisms involved in tolerance, and they can vary by what exactly your target is (what receptor type, or if it's some non-receptor entity like an enzyme, these will have different mechanisms behind tolerance). For receptors, the typical events include changes of receptor number at the membrane (downregulate to reduce signal if your drug is an agonist, upregulate to increase signal in the drug is an antagonist). Additionally, changes in receptor sensitivity or transduction happen (desensitize to reduce signal for an agonist, sensitize for an antagonist). There are several others but we won't talk too much about them here because they're more complex. You can read more about tolerance in the post linked earlier in the paragraph, too.

Figure 1. Homeostatic responses to agonist drugs! Up top: downregulation. The number of receptors on the cell surface is decreased after prolonged exposure to a drug. On the bottom: desensitization. Receptors at the membrane will have a lesser effect on intracellular signaling pathways after prolonged exposure to a drug. (You can visualize the adaptations to antagonists by flipping the arrows in the middle, since they are essentially opposite.)

With prolonged exposure to agonist A, a cell will do some combination of downregulation and desensitization of the affected receptor to maintain homeostasis. But because the cell has adapted in this way, any other agonist that targets this same receptor will also have a lesser effect during this tolerance state. But generic discussion is less fun. Let's talk about the types of cannabinoids.

So let's say someone uses a spice cannabinoid preparation on a regular basis. After regularly stimulating the cannabinoid receptors with the agonist spice drug, their cells will undergo the downregulation and desensitization motions. As is typical for tolerance, with time and repeated exposures, the dose of spice drug required to cause the same effect increases.

Say this person grows tired of the less-effective spice cannabinoid. Maybe they wish to switch back to marijuana, for whatever reason. I don't judge, especially in theoretical situations. So this person, tolerant to spice cannabinoids, then goes back to using marijuana. THC, the principal psychotropic ingredient in marijuana, also works by stimulating the cannabinoid receptors. Since there are fewer and/or less effective cannabinoid receptors around for THC to stimulate, the effect of THC is quite diminished in a user that is tolerant to spice. And this is, in brief, how spice tolerance = marijuana tolerance.

(A caveat: There are nuances here regarding agonist efficacy and potency, but they are generally not dealbreakers for cross-tolerance once the cellular-level adaptations have taken place.)

Wow! Scientopia has some fantastic readers! This year's drive for Donors Choose has so far collected $5734 for students! Go readers!

Several of the projects on the Neurodynamics giving page have been funded! This is really exciting to see. All those kids are going to experience SCIENCE thanks to a bunch of people who kicked in a couple dollars apiece and gathered together to make their projects happen.

We still have a couple of weeks for this year's Donors Choose drive, and Scientopia is in the #2 spot after ScienceBlogs! Another reason Scientopia readers are awesome! How many projects can we fund, how many kids can WIN by the time the challenge is said and done? Only time will tell!

Another project I like quite a bit is some grade-school microbiology. This is too cool- they want to investigate bacteria in their school, see what makes it grow, and generally get some hands-on fun with science. They need some very basic lab supplies. Agar, petri dishes, beakers, stuff that we professionals take for granted. These supplies will also benefit future classes, so your donation goes farther than just this year's students. They need $143.53 to reach their goal. This is not very much if we get together to help these kids. And anyone can help- even a $5 donation is that much closer to reaching their goal! Got a couple bucks to spare this week for some future microbiologists?