Some months back, there was a publication that ended up being highly hyped by the press. Controversy and science by press release ensued. Public relations people had field days hitting all the target demographic periodical outlets. There was a convenient lack of PR for a concurrently published paper with results that could not be more negative. Great situation for people who like to get all fired up about things, useless hype in terms of evidence-based discovery efforts.

The publication in question? A follow-up study by Mithoefer et al describing the long term effects of their MDMA therapy for PTSD, based upon which the press releases make the bold* claim that MDMA augmented therapy has an 89% success rate in treating PTSD.

Herein, I describe the reasons this is an ostentatious conclusion at best.

First, we go back a couple of years

The contested claim is from a story that really gets going in the first phase of their study, which was published back in 2011. So to understand the recent publication, we must start at the beginning.

Briefly, this study used a double-blind design to investigate the effects of MDMA as a psychotherapy adjunct. They recruited 20 subjects, and decided to complicate their study off the bat by using an unbalanced design (unequal sample sizes). Their active drug group was 12 subjects, while the inactive placebo group was 8 subjects. They used common evaluation tools such as the CAPS (clinician-adminstered PTSD scale).

They set out to compare MDMA vs placebo. For the active drug, they administered 125 mg of MDMA at the start of the therapy session, and offered an optional supplemental dose of 62.5 mg MDMA 2-2.5 hours later. (I assume they also offered a supplemental placebo “dose” to the inactive group.) Not all subjects took them up on this, which complicates things further. Pharmacologically speaking, it gets even harder to interpret when you also consider that patients were asked to discontinue use of any psychotherapeutics for the duration of the study. (Withdrawal effects? Rebound effects? How long were they off the meds? We don’t know.) And some patients were given one or two medications to assist recovery after some MDMA+therapy sessions. (What are the effects of these sporadic and inconsistent treatments on consolidating progress made in therapy?)

When you wish to make a big claim, yes, your work is under a level of scrutiny that directly correlates with the size of the claim you intend to make. Their entire study design seems to treat subjects and groups inconsistently, which is a big problem when you want to harp on the strengths of the prospective, double-blind design of the study. Well folks, you have to treat all subjects the same way, too. To the greatest extent possible.

They found plenty of effects, which may or may not be directly related to the primary finding: that people are pretty effin’ good at determining whether or not you gave them MDMA. (As are the study observers.) So much for placebo, so much for the double-blind study.

So, in what reads like a grand gesture of shoulder-shrugging, they offered MDMA +therapy to their placebo group members in an open-label “crossover” phase. Except one placebo subject, whose CAPS score had decreased from 67 to 15, felt satisfied with his or her experience and declined further participation in the study. (The authors note that a second placebo subject experienced a decrease in CAPS score from 54 to 15 after therapy, which later increased to 64. This makes me ponder the effect of the therapy protocol as well as the drug treatment.) They present the data from the crossover phase in a table, arguing this data further demonstrates that MDMA+ therapy improves PTSD symptoms. We can’t tell this claim from a simple effect of more time passing after placebo+therapy sessions, since there is no control group anymore! Also, the way they say these things makes me wonder how exactly they ran their statistics. Well, the way they say things and their inconsistent use of descriptive statistics. (Yes, I lean toward the stats douchery. One kinda has to, in my field.)

These results, as presented, must be considered with a deluge of caveats. Here are a few important ones:

1. Unbalanced design compromises a lot of things, particularly your ability to evaluate the effects of the therapy protocol alone. They seemed much more interested in comparing MDMA vs placebo, not placebo+therapy vs MDMA+therapy. This is one way to look at the problem, but I argue it is the less valid way to look at it.
2. It’s pretty hard to argue for an effect when your control group is not functioning as a control, and your blinding is nonexistent.
3. The non-standardized dosing (the optional additional dose) presents a big confound.
4. The variability of therapy sessions and post-therapy-session drug treatment (with sleep drugs and benzodiazepines, which I view as a considerable blunder) again reduces the validity of the results. We now have a number of confounding factors that distract from the main effect they attempt to demonstrate.
5. This is a tiny study, including just 20 people (12 MDMA, 8 placebo followed by crossover MDMA). Their population was primarily female and primarily survivors of child abuse or sexual trauma, so it’s also a big jump to assume that all populations and all causes of PTSD are going to apply.

That said, with all the limitations and caveats and skepticism, at the end of my first reading of this paper I still thought the data were interesting. Overall, I had the impression that it was worth a further look if they could improve the study design to clear up as many of these initial flaws as possible.

And then the follow-up

So the follow-up is where Science By Press Release took place just recently. Recall, at the end of the study we just analyzed, all participating subjects had received MDMA+therapy. The only acknowledged difference between groups at this point is whether or not the group received placebo+therapy a few months earlier. (Of course, there are many un-acknowledged differences within groups and between groups due to the inconsistent treatment design.)

Now the authors conduct a long term follow-up on their subjects. They received responses from all but three subjects. This gives them a total of 16 subjects (20 to start – 1 declined the open label second phase in the original study – 3 did not complete follow up). They take the data from these 16 individuals and see what can be learned from a more distant timepoint.

Some subjects appear to maintain similar CAPS scores, others seem to show further improvement between the last study timepoint and the long-term follow up, and still others seem to relapse. We see that some subjects completed a third MDMA+therapy session, as well. Importantly, the study authors reveal the full dataset in table format (rather than the graphs presented in the first paper, which were really uninformative without error bars). There is a far wider range of CAPS scores at study entry in the MDMA+therapy group (compared to the group that was originally assigned placebo+therapy and then put into a crossover study).

The authors boast that 8/19 subjects are in psychotherapy at follow-up (a 50% decrease from the 16/19 at study entry). However, they downplay the fact that of the three subjects NOT in therapy, one is in therapy at follow-up. (Though unbalanced, if they wish to compare these things, one could argue this is more than a 50% increase.)

The changes in medication prescriptions seems to be a wash. Some started new prescriptions, some went off prescriptions. I don’t see anything outstanding, and neither did the authors.

Still, they become so bold as to assume that the three subjects who did not complete the CAPS assessment showed improvement without the hard data to back it up and conclude, “Therefore, it may be the case that up to 89% (17/19) of those who received MDMA had long-term improvement in their PTSD symptoms.”

Wow. They quickly get their heads on straight and go back to the data, but that’s really amazing. Even so, they really have shifted to treating these subjects as a set of case studies rather than a treatment group to analyze. They kind of had to, given the lack of control group and not much else to go on. Still, when you shift from a prospective study to a series of case reports, you’re looking at far less powerful results. The press releases certainly don’t reflect that.

Again, it’s an interesting result, but at this point the power of the data is severely reduced- and quite a few of the losses of potential information gained are due to blunders on the part of the authors. That said- do we really need to go around selling early (VERY early) results in a civilian cohort (primarily women, primarily survivors of sexual violence) as the answer to a warfighter/combat trauma audience? That’s cheap and awful.

But lest we forget the conveniently ignored study…

One of the conclusions of this long-term study is clear: people know when you’ve given them MDMA. The subjective effects of the drug create a major problem in doing any kind of blinded study. So the authors of this study used a low dose of MDMA (25 mg + 12.5 mg) as an active placebo, and the same dose of MDMA that was used in the previous study (125 mg + 62.5 mg) as their therapeutic dose. Again they had a low number of subjects split into uneven groups (4 active placebo, 8 full dose MDMA). They claim it was to test safety of the full dose (didn’t the last study do this well enough?) and to enhance recruiting efforts. Huh. They added a third therapy session to their regimen, which differed from the first study.

They effectively solved the blinding problem. Subject and investigator guesses didn’t look a lot better than a random (50/50) chance of being right. So, that’s a plus to the active placebo!

However, there is a massive downside here. Magically, when your subjects can’t tell which experimental group they’re in… your clinical effect disappears. Placebo effect for the win!

Where were the press releases for this study? It was published in the very same issue of J Psychopharmacol as the Science By Press Release (long-term follow-up) study- in fact, it’s the next article in that issue- yet it’s ignored. I only stumbled upon the paper by accident, and was stunned to find the exact opposite of what all the press releases were screaming about.

This is why Science By Press Release sucks. It’s also why double-blind studies are useful, why holding extraordinary claims to high standards is important, and why replicability (especially for small sample size studies) can make or break a finding.

It’s whether you choose to incorporate that new knowledge in your worldview that makes you a Scientist rather than a True Believer in a romanticized idea that sounds great but might just not be right.

Notes:

* this is a politically correct term for "overreaching" or "not really correct"

I really don't intend to sound as uncharitable as I come off. However, I think that if you're going to invest the time and effort, it really should be done right and not halfassed. I see many lost opportunities to learn things here and it's disappointing. It's my opinion that, at this time, there's really not much more to go after on this therapeutic front.

Further reading:

Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. (2011) The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol 25(4):439-52.

Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Martin SF, Yazar-Klosinski B, Michel Y, Brewerton TD, Doblin R. (2013) Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J Psychopharmacol 27(1):28-39.

Oehen P, Traber R, Widmer V, Schnyder U. (2013) A randomized, controlled pilot study of MDMA (± 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). J Psychopharmacol 27(1):40-52.

most of my online presence is on twitter these days, since that format seems to suit my current wavelength of internetting behavior better than the blog setting.

writing this paper while dealing with the random stressful events that life tends to throw at a person from time to time had me blowing off a bit of steam. and i got to thinking about this- often we scientists write papers as small stories of data- "we did A, and that was interesting, so then we did B, which led us to C, and ta-da now we have new knowledge!" but really, it's bullshit. chances are we did B first and asked wtf that result meant, then we did A, and C was something that the lab had been sitting on for a year since it wasn't related to anything that was actually going out for publication at the time.

regardless, we're compelled by convention to make it out like every step of everything was thoroughly justified and went just as planned.

#overlyhonestmethods started as being about revealing the "between the lines" in our methods sections. nobody states that procedures are scheduled around things like lunch breaks or other human elements of our day. but we all know when we read "behavioral assessments were collected at 0900 and 1300" that the authors wanted to sit the fuck down and eat something in the middle of their day. we may report that "we" did some tedious video scoring, but you know it was the editorial "we" - aka, some undergrad did it. sometimes we set out to run ten replicates, and we fuck one up. or something else crazy happened in the middle, like an earthquake or a fire drill. well, now we're reporting nine. but nowhere in the methods will you read "so we kinda blew that first attempt and had to try again" because that's the lab lore, not the scientific literature. because in the scientific literature we're professional, we Totally Meant To Do It That Way.

it's been a ton of fun to see the outpouring of lab lore behind what's in our methods sections. i've seen some snark and sarcasm and written my own, especially regarding statistics (who has reviewed more than a few papers and hasn't run across ONE where the authors were clearly looking for p<0.05, come on). someone somewhere is going to take that literally, and won't that be fun. meanwhile i don't think you'll see a published mention of how the reported incubation time was defined by how long the author spent drinking a cup of afternoon tea, but i think #overlyhonestmethods gets it out there that there are real people doing the science. for the most part we're not as stiff and sterile as our publications (the measure of our careers) make us out to be.

I received a very polite and well-thought out question that I would be remiss in not answering. Sorry it's taken a while, micycle, life has taken several sharp left turns on me this week.

As a principle, I don't give medical advice or anything that might sound like medical advice. I actually skirt the whole giving any kind of advice on the internet thing when it comes to the things people do with their bodies, in favor of informing them what the effects may be. So in response to such a question, I am going to just put some discussion out there about what happens when one is exposed to a fat-soluble molecule and then loses or gains a bunch of weight.

Now, say I've got a friend Joe who has some substantial fat stores and a friend Tim who has lesser fat stores. Joe and Tim happen to be hanging out together in the wrong place at the wrong time, and they are both exposed to the same weight-adjusted dose of a fat-soluble drug, let's call it X.

What is the first thing that X does? It gets into the bloodstream and circulates around the body. As soon as it encounters some fatty tissue, it will preferentially move to the fat and hang out there. The rest is sent around the body, causes whatever effect it may cause on various body systems, is broken down by the liver, and eventually gets sent out of the body.

Who has a greater initial exposure effect- Joe or Tim? Joe has more fat to sequester the X molecules, so the rest of his body is exposed to a lower effective dose immediately. Tim has less fat and more of the X affects his organ systems acutely.

What about in the longer run? Who is worse off? The stored X equilibrates out of the fat over time to provide Joe with a longer duration, lower-level exposure. If X has toxic effects, Joe will likely need continued treatment to counter the effects of X over several weeks. Tim, on the other hand, is much more likely to recover fairly quickly with prompt treatment.

What if Joe loses weight? What will happen? Will he get rid of the X more quickly? If Joe substantially decreases his body fat (not just a pound or two), his fat cells will become smaller. The X will become more concentrated, and the concentration gradient between the blood and fat will become greater. This will favor more X equilibrating from the fat to the bloodstream so that it can be metabolized and cleared. It will also cause an acute toxic syndrome, if X has toxic effects, as the drug once again affects his organ systems. Eventually the blood concentration of drug will drop below the threshold that causes systemic effects/can be detected but this is not going to be immediate. It's worth noting that we're talking a pretty substantial weight loss, and a couple lbs here or there for your average 175-lb adult male would not have such dramatic effects.

What if Joe gains weight? Will he extend the amount of time required to clear the drug? A substantial weight gain would decrease the concentration of X in the fat cell as the fat volume increases inside the cell, but there would still be more X in the fat than in the blood. So the concentration gradient would still favor release of X into the bloodstream. Whether or not the concentration of X in the blood would be below the lowest adverse affect exposure level- or detectable- depends on the amount of X that was stored in the fat to begin with.

How about if Joe just eats a lot of fatty foods- will that slow the release of X into the bloodstream? The factor of interest here is the difference in concentration between X stored in the fat cells and X circulating in the bloodstream. Adding fatty acids to the bloodstream does not change this factor. So, no, eating a lot of fatty foods will not help except in the case of preventing weight loss.

One thing I’ve come to understand about the makeup of the science blogosphere over the last couple of years is this:

Non-academic bloggers are less common than academics because there are greater restrictions on what can and cannot be discussed candidly. There are agreements, there are regulations, and so on, that make it very difficult to describe the day-in and day-out of certain sectors of science. It’s not necessarily nefarious reasoning, but there are interests of all kinds to protect.

However, this does result in science blogging being heavily dominated by voices from the academy with much lesser representation from the substantial non-minority of career tracks that are ironically (in my opinion) labeled “non-traditional”. I am not sure there is any one remedy for this.

I am one such adventurer. Blazer of my own career trail. Or whatever you wanna call it. I have no intentions to return to academia, unless some extraordinary events either turn me back or change my mind. While I don’t imagine these things happening, I can’t rule them out entirely. At present, I am also considering making a transition from a research scientist type position* to a functionally different role in the scientific sphere. This is an even bigger leap, if you ask me- at least in a similar position type, one presumably knows what the fuck one is doing to start with.

While there are few things I can specify, I can state that there are many similar areas of strength and weakness in the sectors I have experienced to date. It is my opinion that the challenges are different depending on where you go- but they do result in roughly the same amount of uncertainty, time expenditure, effort expenditure, etc. And many of the culture-of-science fundamentals seem to remain the same, though the overarching culture and structure/organization of the workplace may be starkly different from that of academia.

Many of the population characteristics of scientists in a given workplace are similar across sectors. And challenges faced by the non-majority (ie, non-white and/or non-male and/or young, etc) are common in every place I’ve seen to date.

For all of you who wish to escape academia… I hear ya. But understand there are upsides and downsides to every place, and no career is going to be free of hurdles. The day it all becomes an easy ride is the day you start doin’ it wrong.

I’m hoping I can expand on some of these thoughts in response to any discussion that may arise, but please understand there is much I cannot expand upon.

*I am overly generalizing here for a reason.

I was recently involved in a discussion about how we ignore signs of poor mental health in high-functioning individuals. The overall impression I got was that we as a society consider the functional output of a person's life/career/etc as a good readout of their overall well-being. I think we all know that's a load of shit, yet it also seems to be generally accepted.

Science seems to be a pretty solid example of this phenomenon, if I may comment based on my own experience. Despite a seemingly neverending and contentious debate over what factors (brand names on the CV, CNS journal pubs, lab pedigrees, etc) make for your favorite brand of career success, I think it's pretty clear that it's high-functioning folks of all types who wind up in the senior scientist positions. Speculate (or argue) all you like about how much they contributed to their career status and how much was luck and etc, fact is they somehow got shit done/got papers out with their names in the list positions that mattered.

Yet we seem to have this (anecdotal, but certainly matching my own experience) preponderance of maladjusted personalities and behavioral issues in these positions, if the disgruntlespheres of grad students and postdocs are any account. And it makes me wonder if it doesn't, on some level, boil down to the fact that we are not paying attention to warning signs that we might notice in a more normally-functioning or impaired-functioning individual.

Consider the high-functioning amphetamine abuser vs the turfed out meth abuser. Who requires the intervention? Obviously both, but do we pay attention to the former? Do we notice?

Consider the person with a personality disorder who has a successful career on the surface but clearly creates a toxic work environment that harms everyone involved, vs the person with a personality disorder who is unable to work. Who do we pay attention to?

The difference is level of functioning.

Consider a mental health diagnosis. Many require the presence of clinically significant impairment of functioning in some important aspect of one's life. Work is only one aspect, first of all. Secondly, what about the population of high-functioning folks who manage somehow to continue lives of quiet desperation, under the cloak of being a high-functioning little worker bee?

Perhaps we need to open our eyes a little more.

Compensating for youngness and femaleness in the workplace. As it stands, I do feel a headwind simply because I'm not a member of the Senior Grayhair Dude club that constitutes 90% of the local investigators.

Allow me to relate a general observation.

Dressed up like an office-dweller, it's a lot more perilous for me to get the hands-on science done, but I get less trampled-over by the administrative people whose purpose (seems to me) is to make my life hell. I look like an administrative person, women can be administrative people, that's OK.

Dressed totally badass for some hands-on science (less sitting-in-an-office-dressy, generally wearing a shirt I can afford to replace easily, carrying my set of science tools, hair tossed back out of the way, etc), stopping by the admin group to inquire about some progress? Now I'm the little girl who has a cute little science project she wants to get done, and how adorable that she's all annoyed at the 5 day lag when everyone else has a 2-day turnaround or less. Patience, little girl. Patience.

Events like today make me feel like I can only be taken seriously on days when I don't have hardcore science to do. Guess how often that happens. I have to multitask the admin and the hands-on science duties all. the. time.

I should mention I am extremely fortunate to have scientific career mentors who take me seriously all the time, who value me for my ideas and my work. And I know they have my back. But some of this overarching culture of science shit I need to navigate on my own. And a lot of it is just bullshit.

I am up to my eyeballs in Super Demanding Long Term Experiment. I made a tentative plan for finishing the remainder of what I'm currently working on. The first type of data collection ends about 2 months into my second year of funding.

Holy shit. The time. It is a-flyin' here.

I was just trying to bear the weight of my own experimental ambition until this hit me. My time on this fellowship is quite finite. While I'm getting great use out of the support and resources and other goodness at my avail in my current place, I have to wonder where this will all lead in the end. I have to keep the end in mind, too. Just more stuff to think about.

A baffling trend came to my attention recently. Surely this can't be right, I thought- people taking high-dose niacin to pass a drug test? Really? I lack the proper words... so I'll just cut to the chase.

The Claim:

Taking high doses of niacin aids in detox and/or passing a drug screen.

Let's deconstruct.

First- what is "detox" anyway?

Generally? Beats the hell out of me. Being a real pharmacologist, I don't buy into this whole "toxins" and "detox" nonsense. But in the context of the claim, the intent is to beat a drug test by somehow reducing the concentration of drug (or drug metabolite) in the bloodstream or urine below the detection limits of the test. I say "bloodstream or urine" because what comes out in the urine is a direct result of stuff getting metabolized from your bloodstream.

Ok, so what is niacin, and what does it do?

Niacin, also known as nicotinic acid, is typically used as an aid in treatment of hypercholesterolemia (high cholesterol). It does this by inhibiting mobilization of free fatty acids to the bloodstream (thereby preventing the liver from turning those free fatty acids into triglycerides, which affect synthesis of the "bad" LDL cholesterol), but it also has some other effects. The most notable side effect of niacin treatment for hypercholesterolemia is flushing, which can be severe enough to prevent people from using niacin regularly enough to keep their cholesterol under control.

Flushing in this context refers to a skin reaction. Niacin use can trigger skin redness, heat, itching, and tingling. The flush may be limited to the face and upper body with a lower dose, though a higher dose might cause more widespread flushing. The mechanism largely considered to be behind this is a vasodilation, or dilation of the small blood vessels near the surface of the skin.

So I guess this is where the "flush" the drug out of your system idea comes from? It sounds like a stretch, in my mind, but that's all I can gather.

How do drugs wind up at detectable concentrations in the bloodstream to begin with?

Pharmacokinetics! I thought it was just one class I had to take some years ago- but no, it just keeps on showing up in real world situations. I wrote a couple posts that might serve as useful background here (Part 1) and here (Part 2).

When you take any drug, it distributes to your body via the bloodstream. Your liver breaks it down, and then you have metabolites circulating until you eliminate them in the urine or feces or sweat or other excretion. The body takes a bit of time to do all this breaking down and elimination, so for a certain time period after drug use, your drug exposure can be determined using a test of urine or blood. This is directly related to the elimination half-life of the drug, and of its metabolites. (And these vary by drug.) You come up with a sensitive enough test, and you can detect vanishingly small quantities of drug or metabolite. This means you end up with a longer period of drug exposure detection.

For drugs that store in the fat, like THC, elimination requires the drug coming out of storage in fat tissue before the liver metabolism step. The slowest step by far is coaxing that fat-soluble drug out of the fat tissue, where it's perfectly happy to just hang out. This is achieved by gradient equilibration. That means that if there is more THC in the fat tissue than the bloodstream, it will follow the concentration gradient to the lower-concentration side, the bloodstream.

Then how does one go about "flushing" the drug molecules from the body?

Simply put? (Using THC as a common example...)

You can't convince all the THC that may be stored up in fat cells to come hang out in the bloodstream for your convenience. There are next to no feasible ways to actively modify the concentration of a drug or its metabolites in your bloodstream, at least in the downward direction. Vasodilation and the increased blood flow that comes with it does not change the concentration of a drug in your bloodstream, does not change the concentration gradient, and does not coax anything out of your tissues. (And we're talking about molecules here. Most especially in the case of fat-soluble molecules, they don't need vasodilation- they get into the tiny blood vessels just fine on their own.)

Bottom line. What will niacin do to decrease or mask the concentrations of drug in the bloodstream?

While niacin is known for causing "flushing" of the skin (and by that I mean redness), I want it to be absolutely clear that it does not "flush" anything else. That means it does not flush the drug molecules from your body. Not only does this regimen fail to have the desired effect, at the doses that I've heard or in attempting this detox myth, this can also fall into the "more harm than good" category. Folks, the only sure way to pass a drug test is to abstain from the drug for a long enough time to eliminate all of it. Period.

____

delayed h/t goes out to WhizBang! for the inspiration.

Genomic Repairman is spearheading a Scientopian effort to study the science of Charlie Sheen. I come to find out, several days late, that I'm in charge of the pharmacology core.

Like I don't have enough paperwork to do.

And hey. I was on some work-related thing last weekend. Don't give me that look.

So I looked into this. Turns out Charlie Sheen claims that he's on a drug. And that drug is Charlie Sheen. Effects appear to be winning, being able to cure diseases with your brain, and several other currently uncharacterized phenomena. Sounds like a pharmacology project to me.

This got me thinking- what kind of drug is Charlie? Any good pharmacology study has a dose-response curve, has a little agonist and a little antagonist action going on to parse out the role of the drug/physiological event/signaling/whatever dependent variable you choose, so surely we need to identify our pharmacological tools before running the experiment. Then it hit me that Charlie Sheen seems to be acting as an agonist *and* an antagonist. We're identifying whole new avenues of pharmacology here, people.

Scientopia: Winning.

Oh, science. I feel like I'm pedaling harder and harder, but I also seem to be dropping gears quickly. It takes so much more just to keep pace. One disruption today and I felt like I was going to hit the ground face first.

I keep meaning to get a few more things organized so I can plan a little time away to refresh and reset. Something always comes up and keeps me from even thinking about time away.

I feel insecure in my ability to keep this up, exhausted of energy (I put it all into this and I need a break!), and even the piles upon piles of cool data rolling in are not feeling like enough to sustain me through this particularly intense period. I'm taking down barriers only seconds before my science blows past them.

On one hand, it's really great that I'm making this kind of progress and learning to handle these kinds of challenges. Kind of a make-up for some lost time/missed opportunities in a previous career stage. The other hand is punching me in the back of the head.