I haven’t done a drug Sunday in a while, but I feel as though I should, given the heinousness of my previous post.  You see, I have some sort of anxiety disorder or something which appears to run in my family.  I usually work this out with running but haven’t been able to do that for a while and, consequently, the anxiety gets the better of me.  NOW, a consequence of said anxiety is insomnia – which is essentially the most annoying side effect.  (Most of my family are insomniacs.  At any given point, I could wake up and find some member of my family awake in the house, watching TV or playing on the internets or, in the case of the grandparents, smoking cigarettes reading newspapers…)

Whatever.  The short of the long of it is sometimes I can’t sleep and so I turn to chemistry to help me.  Ambien, consequently, plays an infrequent roll in my life.  As I have said before, I’m totally sXe (hahah) and have little experience with recreational drugs.  However, since I received my first prescription for Ambien in college, I have collected a few unusual stories:

• I woke up with bruises on my knees and several forts constructed out of couch cushions in my living room.
• I woke up face down in a pint of melted and congealed ice cream in my living room wearing nothing but a cashmere frock coat.
• I woke up to discover that the walls of my room had been covered in aluminum foil.

That’s just to name a few…  needless to say, I usually take the drug only when I have little other discourse and there is someone else at home.  My wife, Mrs. Finchsigmate, is usually my trip sitter – though she’s generally asleep by the time I realize it’s either going to be an Ambien night or no sleeping at all.

ANYWAY, not that’s out of the way, let’s discuss Zolpidem, the chemical also known as Ambien.

Synthesis of Zolpidem can be accomplished in a fairly steppy but simple synthesis starting with the commercially available Methylacetophenone:

The mechanism of action of Zolpidem works by potentiating γ-Aminobutyric acid (GABA) by binding to benzodiazepine receptors, though the drug bares no structural resemblance to benzodiazepines (well… not very much).  The patent on the drug was held by Sanofi-Aventis and is now available in generic form.  A new formulation called Ambien CR supposedly extends the very short 2 hour half life, allowing patients to “sleep through the night” by retarding the rate of drug release from the capsule in the digestive system.

Ambien sales before generic were 2.1 billion per annum, the Ambien CR formlulation as of 2008 rakes in almost 900 million per annum – so Sanofi isn’t starving having lost their cash cow.

But, by far, the most notorious thing about Zolpidem is the associated sleep walking and amnesia.  My anecdotes above are drops int he pond of larger reports that the drug has been associated with unusual behaviors that place the victim in precarious and even deadly situations.  Why this drug is even allowed on the market at all is beyond me but it’s certainly effective.

Zolpidem is a drug of abuse and trip reports have been extensively loged at Erowid.  From my own personal experience, hallucinations are rare but can be fantastic (in the sense that they give the illusion of rather incredible things occurring – such as seeing the television you’re watching, while waiting for the drug to kick in, fly into the air and bounce off the ceiling like a balloon.)

As new details emerge in the fatal UCLA lab fire that killed Sheri Sangji, a research assistant in Patrick Harran’s lab, it becomes more evident that UCLA is a dysfunctional department in an environment where the burden of responsibility is placed upon everyone and everything other than that of the university or the department.  The slow decline of UCLA and recent high profile departures suggest a department of infighting and low morale.  From the LA Times:

In electronic missives to university colleagues, Harran complained that UCLA had all but hung him out to dry in the press. In one e-mail, he said that reports in two chemical industry publications “read like an indictment, without having the facts.”

In another, he took issue with a UCLA investigator’s report, which was detailed in a March 1 story in The Times. The report, citing previous lab deficiencies that had gone unfixed, made it “sound like I deliberately did not adhere to policy” and was part of a “culture of neglect,” he wrote.

According to the same article a similar, though non-lethal, incident occurred at the school not but a few weeks ago.

While I pick on UCLA (rightly so) the issue is far more systematic and, as anyone who has gone through graduate school knows, safety training is almost non existent.  I rarely see lab coats on in my own lab, though it’s hypothetically required.  I generally never wore a lab coat until I got an asskickity one as a gift from my boss for making a website for him.  If custom lab coats get people to wear them, then that’s what schools should offer!

I contacted my senator about this issue.  I’ve had good relations with his office and am a strong supporter, but he was unreceptive to the idea.  If you could, for just a moment, pull your cell phone out and call these senators and reference the LA Times article above about the need for universities, who receive federal research grants for science, to provide comprehensive training to all laboratory workers.  You may well do something to help prevent this shit from happening again.  Indeed, maybe even to yourself:

The first time you contact an “almighty” senator, you will likely hear the voice of one of his or her staff members. This is quite fine, they’ll dutifully report to the senator any grievances you have so long as they aren’t too grandpa Simpson.

For tips, you would start like you were calling an insurance office asking for information. Introduce yourself, tell them what you do and how you are relevant and then, quite politely, say something like:

I’m not sure if you’re aware of the recent laboratory fire that killed a 23 year old UCLA lab assistant, but having gone/been/are in graduate school I can attest that the safety measures that surrounded this death are all too common. I feel as though because these schools all receive federal funding, it should be within the purview of the senate to require, as a condition of receiving federal funding, to provide life saving training to students and employees. You can read the latest in a recent LA Times article…

Hutchison’s people will likely ponder if that’s really within the purview of the feds and wonder if it’s even worth considering (such is the stalwart nature of Republicans). I would anticipate little to no static from any of the other Democratic senators. You will likely not hear back, but you will still be heard, I assure you. I have spoken with the offices of my senators many times.

NOW DO IT! Or I’ll give you swine flu.

UPDATE:  Answer this poll question!

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A while back I was lucky enough to be accidentally selected to take a big shot from big pharma out to lunch while she was visiting. I say accidentally, because I’ve been a very vocal critic of big pharma’s business model, going so far as to actually do a seminar on the subject the first year I was in graduate school (kids, don’t do that.) My position isn’t that Big Pharma is evil and they’re out to get you, it’s that they’re big, stupid useless machines that pump out gobs of fluorinated shit for metabolic syndrome and boners and buy up little companies before their quarterly reports are up. None of them are hiring like they were a few years ago. Indeed, getting a job at these huge companies isn’t likely going to be the outcome for most people, regardless of the lab you work in. So, I took this lunch time opportunity to propose my own, rather arrogant opinion: It’s because they keep recruiting from Dave Evan’s lab. And Barry Trost’s lab. And Sam Danishefsky’s lab…. you know… as I so politely put it, the Legends of Total Synthesis. Of course, this doesn’t mean that all drug companies have stalled. Some how, we continue to get new drugs – they’re just not being made “in house” by big pharma. Look at my gheto-graph of New Drug Applications by year:

If you’ll forgive the gayness of my chart, I pulled that data here, from the very government those drug companies have worked so hard to create for us. The blue line indicates the number of NDAs approved and, apparently, the only people that can really tell the difference between “the good years and the bad years” are John Lechleiter, Richard Clark, Jeff Kindler and/or any other douche bag that is lucky enough to be promoted to “transient CEO of big pharma for a few months.” An average of 90 ± 20. With a huge boom in the late 90’s where, I presume, most of those are still covered by the more realistic “25 year patents”.

I remember back in 2002ish at Lilly when Big Syd Taurel got on the jumbotron in building 78 (there really is a huge screen and projector in the atrium – at least there was at the time) and announced that Lilly was going to enter into a hiring freeze because someone fucked up and lost the patent to Prozac before they could wring a few last good years out of it. Since then, it’s been a litany of unproven excuses like “It costs a BILLION dollars to discover a new drug and the Canadian reimportation/corporate taxes/generic competition/short patent/turrists/life is just draining all our money away and we’re operating on PENNIES, PENNIES I TELL YOU” and so on, yet – we can see from our friend the graph, that apparently some companies are doing just fine.

But I was discussing the legends of total synthesis contribution to this. Pardon the digression. The problem, as I see it, is that people who work in these labs go on to fill the ranks of big pharma, who have done nothing, while little upstarts, which are filled with people from “lesser groups” at “lesser schools” appear to be doing alright. WTF gives? Is it… possibly… that total synthesis MAY NOT be the best training for drug discovery (heresy!). (Tip: the stock excuse is that you hear more from little companies because they’re more likely to announce their discoveries faster. Apparently, Big Pharma sits on ALL news, not just the bad news.) Or has Big Pharma academically inbred it self into Appalachian style banjo plucking retardation? It could be both, of course.

I don’t think it’s just me, but it could be: does it seem like the groups with the largest anti-bio vibe are either material groups or total synthesis groups? While the obvious pitfalls of not appreciating the delicate biochemistry of the organisms you intend on eradicating may become apparent all too soon to the material folk, being anti-bio in a total synthesis lab is stupid, counter productive, and very prevalent. The new “multidisciplinary” action that compose 30% of Big Pharma powerpoint slides isn’t coming through in their hiring practices as they keep recruiting from labs that wouldn’t be able to find the active site of a protein if it were docked to the fatty part of their ass. It would be more logical to approach people who work in multidisciplinary labs, that make and model enzyme substrates – people who think like a biochemist but are trained as an organic chemist. The target in drug discovery is never known at the onset – if it were, the discovery process would be a lot easier. This is clearly not the case in total synthesis, where the target you’re synthesizing is known from day one and your mission is to make it, live or die trying.

So I dropped these things on her and got back the stock responses which I’ve heard before (she is a proud alumni of the Evan’s lab, unsurprisingly)- “we need people who can think critically about chemistry.” To which I obviously replied, “I would think anyone obtaining a PhD in chemistry should have that ability.”

Her answer was glib. “You’d like to think so…” suggesting, some how biochemists lack a certain part of their brain that performs these advanced critical thinking tasks and are awarded PhDs on the basis of “good, honest hard work if not pointless work.” Or, if I were to be even more cynical, that people who are in these legendary groups are always going to be critical thinkers and everyone else is too questionable to spend time interviewing. Which is bullshit, of course, but I’m just being cynical here.

Obviously, if you want synthetic chemists, you’ll want to hire people with bench experience, but there’s no need to hire people from the same 10 or 15 groups. Apparently, anyone can use SciFinder now, so it’s largely unneeded to get people with broad encyclopedia knowledge of reactions and, at any rate, at some point companies need to look internally to determine why they are failing and, amongst other atrocious practices (including over use of direct-to-consumer marketing, out sourcing R&D and process to developing countries with governments that are blind to intellectual property theft, excessive executive compensation packages and top heavy managment structures… so on and so forth) they need to consider that they’re recruiting researchers poorly and their hiring strategy is pulling a homogenous pool of people and they’re doing it because 1. the people hiring were from those groups and 2. trying new shit is just not something huge, stupid drug companies do well or do quickly.

I’ll end this rather long post with a cautionary disclaimer – I don’t do total synthesis but I’m also not interested in working for Big Pharma. I have no outward interest in these companies suddenly recruiting from… say… oh… some lab at Cal Tech. I also think TS is a great area to prepare chemists for work in drug companies – the issue is homogeneity and inbreeding, not that they’re failing to find quality people.

So, out of about 375 of you (about 25% of Nature’s respondents) about 35% say that availability not being a factor you would essentially use some form of prescription drug to give yourself an intellectual boost, which is not too far above what Nature polled for people in the age group I assume my readership is in.

I mean, possibly 10% higher, but these polls are horribly inaccurate anyway, so I’ll just call everything even and say, maybe if availability weren’t an issue, But it’s not as high as another number. Apparently, almost 60% of you have already tried a drug for recreational purposes already.

Now… that’s interesting.

I wouldn’t do it myself, actually, for a very singular and almost arbitrary reason: I can’t stand stimulants. I suppose Provagil isn’t really a stimulant, but I hate everything that prevents me from getting to sleep. I enjoy the taste of delicious warm coffee, so I do drink caffeine, but never after 4pm. I didn’t use the shit to stay awake as an undergrad and I don’t use it to stay awake now. Sleepiness is God’s gift to you. It means you’ve done a good day’s worth of work. Maybe that’s not a very good reason not to do it. I suppose there are no higher moral reasons in me that would keep me from taking any drugs to accomplish more in the lab, but let’s be frank, most of the problems I have with illegal drugs are non-existent:

1. You’re using your own machinery. “Drugs” advance what you have – they don’t give you more. It’s not like they build gray matter, they just make it more avaliable
2. These are high quality pharmaceuticals, not crack rocks. Quality wouldn’t be an issue
3. Using FDA approved drugs does not perpetuate cross boarder illegal trade and perpetuate street violence
4. I am not providing any more impetus to continue to fund the DEA than I absolutely need to

There you have it. I don’t know if I can condone the use of drugs for performance enhancing purposes, but I don’t think I would mind if someone were using them. Unless someone can point out why I should care.

By now, everyone has heard about scientists using drugs to become smarter, better, faster like the Kanye West. For those under rocks, 20% of “scientists” have admitted to using performance enhancing drugs (a.k.a. Nootropics)- drugs which I’ve actually blogged about like Modafinil and other’s I have yet touched, like Ritalin.

The 1 in 5 number is a bit surprising, but it brought up a number of well written and freely accessible deliberations on the use of such drugs here. (Note the persistence of the age old practice of addressing letters to the editor as SIR. I demand righteous indignation be heaped upon them out of fairness for the abuses I’ve taken.)

Whatever. To the chemist, most of these drugs are readily accessible compounds. Only the fear of ingesting stuff you made in the lab must be overcome (which is honestly about as close as “not accessible” as one can come), but, I hypothesize, for most people availability is a major hurdle to doing drugs. So, let me ask you this question: I’ll qualify it by saying that you’d use it only in cases where it is necessary, but, let’s say you had a bottle of Provagil all legally obtained. You needed it to finish up an experiment (which you could do the next day, though that wouldn’t be ideal) would you take a pill to help you finish up your work through the night? I’ll do a follow up in a week or so as the votes trickle in. (I appreciate that this is a bit of a trickier question than, “which way is it spinning” but perhaps I could convince a few hundred of you to vote here. I mean… you’re clicking a button here. JUST VOTE. Don’t think. Pretend this is Chicago or something.)

You know, you could abuse the shit out them too… but the point is, you’ve got the bottle already – why not?

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