Pharma Bashing

Ben Goldacre writes the Bad Science column for the Guardian newspaper in the U.K. and mostly he writes about pseudo-science because, as he puts it, “pulling apart bad science is the best teaching gimmick I know for explaining how good science works”. He has just put out a book called Bad Pharma, putting the foreword on his blog, an excerpt appeared in the Guardian and he put up a video of a TED talk he gave. So he is getting it out there.

The book, as a brief summary, takes the pharmaceutical industry to task for its clinical trial practices, wherein it skews the trials to favor their candidate, hides the results of unfavorable trials, covering up side effects and persuading doctors to prescribe their drug once it comes to market with misleading data published in industry sponsored journals. The game is rigged in favor of the big companies who then rake in the enormous profits.

Some people dispute this claim and John LaMattina put up his own take on the book and its contents.

So before my comments, my disclaimer. I suppose I am one involved in the pharmaceutical industry , though I have never worked for one directly, working for a industry contractor on research projects for several years, but these days I am more an interested observer, as I am at a non-profit research institute. I am also not by any means an expert on how clinical trials are run, exactly how things get approved for use or indeed very much at all about the ins and outs of the process. But I have a general idea.

Now the pharmaceutical industry have not done themselves any favors here. They have done all the things that Dr. Goldacre accuses them of, but the blanket statement that the whole industry is out to trick doctors and patients into taking their drugs is extreme to say the least. Pharmaceuticals in various forms have improved the lives of millions of people, saved them from death. Drug candidates are carefully vetted for efficacy and safety – more and more these days as there are so many treatments already available. Clinical trials are not just run against placebo but for approval, drugs need to show an improvement over a standard treatment. In short, that the system is occasionally circumvented does not mean the system does not fundamentally work.

If you look at it from the pharmaceutical company’s view, you can see why these sorts of things happen. Projects begin because there is a medical need for a treatment – essentially a gap in the market. So scientists work to come up with something that will meet that need. But the process of working that out is long and difficult and so many things can go wrong along the way. Worse still, the further along the path you get the more expensive the next step. A phase I failure is a disappointment for sure but it is a minor inconvenience compared with a late stage Phase III failure. Drug development is a high risk venture and there is no pay-off without a final marketable product. So at a certain point, the aim becomes the finish line of FDA approval. Anything that can lower the obstacles in the way would seem like an obvious route to take. Far from the drug companies preying upon the vulnerable and pushing through drugs that should not be, they suffer some dramatic failures – ask anyone in the Alzheimer’s field. Indeed if the system is set up to favor the drug companies, why is there so much talk of the barren drug pipelines and lack of new drug approvals? Pharmaceuticals have always been a high risk high pay-off investment but the risk seems to have risen and the prospect of a big pay-off seems to be receding.

Interestingly, as I was writing this (and re-writing it – curse that wordpress log-off), I came across Matt Herper’s post on Glaxo’s greater clinical trial transparency. This shows two things to me: firstly, that the pharmaceutical industry is aware of its image problem and are prepared to do something to counteract that perception. But also, that there are the problems talked about by Dr. Goldacre, with prominent doctors paid to talk up a new drug from GSK or pushing unapproved uses. That they are taking steps to reassure the general public can only be a good thing.

Quick addition: Ben Goldacre posted his response to GSK’s proposal and he voices some doubts about whether they will actually go through with it.

Local Guy Makes Good

Despite my stance as a Nobel curmudgeon, I will still stand up and salute a local scientist who did OK. Dr. Robert Lefkowitz of Duke Medical Center and Howard Hughes Medical Institute picked up the Nobel prize in chemistry today, along with Stanford’s Brian Kobilka for their work on G Protein-Coupled Receptors (GPCRs), an area of immense importance in the drug development area and also one that intersects with my own current work.

Congratulations to both men.

Shaking off the Jet Lag

There was (if you didn’t notice) a little lapse in the usual sporadic pace of blogging, as I was away on summer vacation. We visited the city of San Francisco, California and did lots of very touristy things and had an excellent time.

The blog I probably would have written over my absence would have been about the Sheri Sangji case, but some sterling work by ChemBark, ChemJobber and, especially, Jyllian Kemsley (surely that should be Chemsley?) covered all bases and I have little to add to their words. Thanks, guys.

I mention my trip to California in particular as when we got back to home to North Carolina, there was the inevitable jet lag. I don’t know if it is just getting older, but the time changes seem to be harder to get over than there used to be. Even the one hour shift to daylight saving time from standard time knocks me off kilter for a few days. As it happened the transition to Pacific time was a breeze – effectively you sleep in and we tended to be heading to bed early anyway after a busy day wandering around and looking at stuff (as the fig allows, at least!). But back home, suddenly it is get up really early and go to bed really early. Even after the weekend, I was still wide awake at 1 in the morning, wondering how I was going to make it into work at a reasonable hour. Some dragging was involved.

It seemed to us that we were in a loop, we couldn’t get up as early as usual, so we would not feel sleepy enough at bed-time and stay up too late and have trouble getting up next day. So to break the cycle, my wife suggested a single dose of melatonin to get us back on schedule.

The over-the-counter medicine was a low dose (and pleasantly orange flavored too) but it really did do the trick of making me feel sleepy ahead of midnight. Which meant I could get up earlier, get back into the routine.

So what is this miracle? Well, it is a neurotransmitter made in the pineal gland which is involved in our normal sleep-wake cycle. Typically, levels rise through the evening and fall in the morning. It is affected by the light (and contributes to seasonal disorders when you live somewhere that gets dark early in the winter). That is a reason not to turn full lights on when you wake up in the night (or even at bed time) because you don’t want the melatonin levels to drop before you are back in bed and snoozing.

Interestingly, a study was done of the use of melatonin on sleep disorders and it concluded “There is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction, such as jet lag and shiftwork disorder. There is evidence that melatonin is safe with short term use.”

I definitely felt a sleepiness when I had my little pill. Was it the placebo effect? I’ll add that I went to bed early but read in bed for a while. That usually has a soporific effect unrelated to the quality of the reading material. So the idea of acting upon the problem got the circadian rhythm back on course? Just allowed us to break the cycle? That would seem to be the case.

Just as well, as school starts again next week – and that involves an even earlier start!

Perils of the Garden: the Common Fig

After my earlier post on the perils of poison ivy in the winter, here is a slightly less fraught tale of garden chemical hazards. Listing the most common complaints of the outdoors in summer in North Carolina, the fig would be low on most lists. Mosquitoes, snakes, spiders, the heat, the rampant weeds, all of these would rank ahead. But after doing some work in the garden last week, I came back inside and found my eye sore to the touch. I figured the culprit to be one of those all too common weeds, but my horticulturist wife saw it differently (and she knows her poison ivy!). Because among the work I had been doing out there was the arduous task of sampling the fruits of our splendid fig tree. When she pointed this out, I recalled taking the fruit and some white sap running down my fingers. All it took from there was for me to wipe at my eye, for fig sap is a known irritant.

Fortunately, it is relatively mild and some aloe and a day or two and all was well. No doctor visit for steroids required. But I was curious about the irritant in fig sap so I did a little digging.

One thing I found was about the photoactive ingredients of the sap, psoralen and bergapten, present in the sap but not the fruit.

These compounds increase your sensitivity to light and have been used as tanning activators, though that comes with a higher risk for skin cancer. Seems like a rough trade-off.

In addition to those furocoumarins, there are also some triterpenoids. A paper on PubMed talks about them. They note that “calotropenyl acetate, methyl maslinate and lupeol acetate showed potent and persistent irritant effects”. Just to show how complex this gets, lupeol is listed as an anti-inflammatory.

Though it just affected the membranes around my eyes, it can get much worse if you are allergic or sensitive to the sap or of course if you work with it. Such complaints are common among pickers and handlers. Fig latex (i.e. the milky sap) has been used in medicinal preparations for skin complaints and was also an ingredient in a household detergent in central America until too many complaints of reactions led to its withdrawal.

It just goes to show it is hard to know where you might be safe out in the garden. Best to run back inside, wash your hands and enjoys the figs.

Defining Cannabimimetic

Following up my previous post, I went into the proposed legislation and found the relevant section, which I reproduce here:

SEC. 1152. ADDITION OF SYNTHETIC DRUGS TO SCHEDULE I OF THE CONTROLLED SUBSTANCES ACT.

(a) Cannabimimetic Agents- Schedule I, as set forth in section 202(c) of the Controlled Substances Act (21 U.S.C. 812(c)) is amended by adding at the end the following:

‘(d)(1) Unless specifically exempted or unless listed in another schedule, any material, compound, mixture, or preparation which contains any quantity of cannabimimetic agents, or which contains their salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation.

‘(2) In paragraph (1):

‘(A) The term ‘cannabimimetic agents’ means any substance that is a cannabinoid receptor type 1 (CB1 receptor) agonist as demonstrated by binding studies and functional assays within any of the following structural classes:

‘(i) 2-(3-hydroxycyclohexyl)phenol with substitution at the 5-position of the phenolic ring by alkyl or alkenyl, whether or not substituted on the cyclohexyl ring to any extent.

‘(ii) 3-(1-naphthoyl)indole or 3-(1-naphthylmethane)indole by substitution at the nitrogen atom of the indole ring, whether or not further substituted on the indole ring to any extent, whether or not substituted on the naphthoyl or naphthyl ring to any extent.

‘(iii) 3-(1-naphthoyl)pyrrole by substitution at the nitrogen atom of the pyrrole ring, whether or not further substituted in the pyrrole ring to any extent, whether or not substituted on the naphthoyl ring to any extent.

‘(iv) 1-(1-naphthylmethylene)indene by substitution of the 3-position of the indene ring, whether or not further substituted in the indene ring to any extent, whether or not substituted on the naphthyl ring to any extent.

‘(v) 3-phenylacetylindole or 3-benzoylindole by substitution at the nitrogen atom of the indole ring, whether or not further substituted in the indole ring to any extent, whether or not substituted on the phenyl ring to any extent.

‘(B) Such term includes–

‘(i) 5-(1,1-dimethylheptyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol (CP-47,497);

‘(ii) 5-(1,1-dimethyloctyl)-2-[(1R,3S)-3-hydroxycyclohexyl]-phenol (cannabicyclohexanol or CP-47,497 C8-homolog);

‘(iii) 1-pentyl-3-(1-naphthoyl)indole (JWH-018 and AM678);

‘(iv) 1-butyl-3-(1-naphthoyl)indole (JWH-073);

‘(v) 1-hexyl-3-(1-naphthoyl)indole (JWH-019);

‘(vi) 1-[2-(4-morpholinyl)ethyl]-3-(1-naphthoyl)indole (JWH-200);

‘(vii) 1-pentyl-3-(2-methoxyphenylacetyl)indole (JWH-250);

‘(viii) 1-pentyl-3-[1-(4-methoxynaphthoyl)]indole (JWH-081);

‘(ix) 1-pentyl-3-(4-methyl-1-naphthoyl)indole (JWH-122);

‘(x) 1-pentyl-3-(4-chloro-1-naphthoyl)indole (JWH-398);

‘(xi) 1-(5-fluoropentyl)-3-(1-naphthoyl)indole (AM2201);

‘(xii) 1-(5-fluoropentyl)-3-(2-iodobenzoyl)indole (AM694);

‘(xiii) 1-pentyl-3-[(4-methoxy)-benzoyl]indole (SR-19 and RCS-4);

‘(xiv) 1-cyclohexylethyl-3-(2-methoxyphenylacetyl)indole (SR-18 and RCS-8); and

‘(xv) 1-pentyl-3-(2-chlorophenylacetyl)indole (JWH-203).’.

(b) Other Drugs- Schedule I of section 202(c) of the Controlled Substances Act (21 U.S.C. 812(c)) is amended in subsection (c) by adding at the end the following:

‘(18) 4-methylmethcathinone (Mephedrone).

‘(19) 3,4-methylenedioxypyrovalerone (MDPV).

‘(20) 2-(2,5-Dimethoxy-4-ethylphenyl)ethanamine (2C-E).

‘(21) 2-(2,5-Dimethoxy-4-methylphenyl)ethanamine (2C-D).

‘(22) 2-(4-Chloro-2,5-dimethoxyphenyl)ethanamine (2C-C).

‘(23) 2-(4-Iodo-2,5-dimethoxyphenyl)ethanamine (2C-I).

‘(24) 2-[4-(Ethylthio)-2,5-dimethoxyphenyl]ethanamine (2C-T-2).

‘(25) 2-[4-(Isopropylthio)-2,5-dimethoxyphenyl]ethanamine (2C-T-4).

‘(26) 2-(2,5-Dimethoxyphenyl)ethanamine (2C-H).

‘(27) 2-(2,5-Dimethoxy-4-nitro-phenyl)ethanamine (2C-N).

‘(28) 2-(2,5-Dimethoxy-4-(n)-propylphenyl)ethanamine (2C-P).’.

SEC. 1153. TEMPORARY SCHEDULING TO AVOID IMMINENT HAZARDS TO PUBLIC SAFETY EXPANSION.

Section 201(h)(2) of the Controlled Substances Act (21 U.S.C. 811(h)(2)) is amended–

(1) by striking ‘one year’ and inserting ‘2 years’; and

(2) by striking ‘six months’ and inserting ‘1 year’.

My first impression is that it reads like a patent. That is likely the best angle to take on this, something broad enough to cover what might be made but narrow enough to avoid over-reaching and impinging upon unrelated research work.


It looks like they covered the basic structural motifs seen in CP-47,497 (along with some related compounds like HU-243) and JWH-018, along with some related JWH indoles. I was glad to see that they were quite careful with the wording on the indoles, so that clear derivatives of the CB agonists would be covered but not necessarily all indole chemistry. They included the pyrroles and indenes but no specific examples of those, which I thought a weakness of the statement. The broad number of examples in the indoles leads me to think they are basing it on examples found in incense and bath salt products. I will also applaud the inclusion of a specific phrase that includes the measured biological activity (in binding and functional assays), which is to me at least the most defining feature of a CB agonist.

New Banned Substance List

Came across this post from Neurobonkers, talking about 26 new additions to the Schedule 1 list of chemicals. Quite a lot of them are cannabinoids from either the JWH series or AM series, with some which I thought were already on the list (JWH-018, for example), from an initial effort to stem the tide as it were which put 5 such compounds on the list. Consulting of all things the Wikipedia page for JWH-018, I find that they were indeed put on Schedule 1 in November 2010 but only temporarily while further studies were done and this had expired.

The Neurobonkers article makes some good points, but I would hardly classify the DEA move here as “knee-jerk”. The people making things like Spice and K2 have shown a high level of sophistication in what they choose to add to their product (picking out the more active compounds, showing they have read up on Huffman’s J Med Chem papers). The number of available known active cannabinoids is large and realistically this is not much more than a speed bump. As I noted already, they made the first rather tentative step in regulating these chemicals in 2010 and have been struggling with how to deal with this growing problem.

And it is a problem. I got the impression of the neurobonkers folks saying that this is the man coming down on their fun, but the strange problem here is that the illegal drug (THC in marijuana) is notably safer to use than the until-now legal highs. THC is only a partial agonist, which means its effects on the brain and body are necessarily limited. It is hard (maybe impossible) to actually overdose on THC. The trouble is that medicinal chemistry has been able to exceed the natural potency – nature is so very good at making things only as potent as it needs to be – the synthetic cannabinoids are full agonists and are thus much more potent; the danger in using them is greater, the potential for overdose is higher and the anecdotal evidence of extended highs and racing heart rates is worrying. Putting them into Schedule 1, using the time to study their effects and even extending the time allowed to study them (an additional provision in the new legislation) would make our understanding of these substances much more complete.

Some of that work is ongoing. I know colleagues here who are working on both the pharmacology of the synthetic cannabinoids and also on the analysis of the incense/ bath salts samples in order to determine what is in them. This is important because even now the newest batches of K2 incense will have an altered mix of active ingredients, which are all still legal, if not any less potentially dangerous.

Though there is some effort included in the new legislation to combat the moving target here, to wit a definition of “cannabamimetic agents”. I am digging into the bill itself (it is Section D if you are feeling brave enough to join me) and I will have to comment on that once I have digested it. My short version is that this is a potential mine field for both law makers and chemists – though at least they don’t appear to have simply made an indole a cannabamimetic.

In addition to the 15 cannabinoids, some cathinones and some C2 compounds were included. I don’t know much about either, though as the cathinones are amphetamine based it is not a big surprise to see them on the list. The C2 compounds I hadn’t read about before. They are the work of Alexander Shulgin, phenethylamines related to mescaline, psychedelics and hallucinogenics. Included due to a case of accidental overdose, it strikes me that these are less of a public danger than the other two classes, but studies should bear this out.

Herper’s Blog on Vaccines and Autism

I just read Matthew Herper’s piece on Forbes about vaccines and autism and about Donald Trump and Bill Gates. And also about why it is so dangerous for famous people to use their position to talk about things they do not fully understand.

To summarize, Trump talked about the excessive number of vaccines given to babies, how it could lead to autism which has risen greatly over the last decades. He is not the first to do so, but the pivotal study on autism and vaccines by Andrew Wakefield has been withdrawn as fraudulent – there simply is no link between the two. Bill Gates (who’s work with his foundation means he is a lot better informed on this issue than Donald Trump) clarified that point rather succinctly – that people not vaccinating their kids against measles means that some kids will get measles and some of those kids will die.

The part of Herper’s piece that really got me was this quote:

These kinds of worries hit us right in parts of our brains that have little to do with the analysis of data from scientific studies. When my kids got their shots, I remember being nervous about the autism link, even though I didn’t believe it. Because when you’re holding an infant, the thought that you might be doing something to hurt them is simply terrifying.

It got me because I have been there. And more than that, I got to think back on that moment later because my eldest son was diagnosed with mild autism. He’s doing fine now, but he did not even begin to speak until he was 3 years old. He seems to be making up for that now. He has some trouble concentrating on stuff he doesn’t particularly want to do (like homework) and you can barely drag him away from something that he does want to do. But he is doing well.

Do I blame the vaccines? I do not. Because I can look back also at my family tree, as well as my wife’s family tree, and we can see some signs of autistic spectrum behavior in our ancestors and even a little in ourselves. No, I think the rise in the number of autistic cases is due to detection not increased causation, that the area has recognized a spectrum of autistic disorders, many of which would not have been seen as such years ago, merely eccentric or quirky.

What we don’t need is people spouting nonsense they have no business spouting.