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.)