ECT in Nixonland

I've just finished Nixonland, Rick Perlstein's history of the 1960s. Some things I learned: Richard Nixon was a genius, albeit an evil one; the 1960s never ended; Rick Perlstein is my new favourite political author.

The book also reminded me of a sad episode in the history of psychiatry.

George McGovern ran against Nixon as the Democratic candidate for President in 1972. He was essentially the Obama of the 60s generation: unashamedly liberal and intellectual, he unseated the "established" candidate, Hubert Humphrey, to clinch the Democrat's nomination after a bitter primary campaign thanks to his idealistic young grass-roots.

McGovern had difficulty choosing his vice-presidential running mate, and eventually chose a little-known Senator from Missouri, Thomas Eagleton (left in the photo). It seemed a safe enough choice. Until Eagleton's first press conference.

Eagleton revealed that he'd been treated in a psychiatric hospital for "exhaustion" - everyone knew he meant clinical depression - three times, and that he had received electroconvulsive therapy twice. McGovern hadn't known this when he picked him.

From there it was all downhill. McGovern initially said he backed Eagleton "1000%". But to some, the idea of putting someone who'd had shock therapy a heartbeat away from the Presidency was unacceptable, and after two weeks of gossip, McGovern dropped him from the ticket.

Perlstein notes that this move wrecked McGovern's image as the idealistic and authentic alternative to politics-as-usual. Polls showed that Americans overwhelmingly trusted Nixon over McGovern, even as the facts about Watergate were emerging. Nixon won a landslide.

Good News for Armchair Neuropathologists

Ever wanted to crack the mysteries of the brain? Dreamed of discovering the cause of mental illness?

Well, now, you can - or, at any rate, you can try - and you can do it from the comfort of your own home, thanks to the new Stanley Neuropathology Consortium Integrative Database.

Just register (it's free and instant) and you get access to a pool of data derived from the Stanley Neuropathology Consortium brain collection. The collection comprises 60 frozen brains - 15 each from people with schizophrenia, bipolar disorder, and clinical depression, and 15 "normals".

In a Neuropsychopharmacology paper announcing the project, administrators Sanghyeon Kim and Maree Webster point out that

Data sharing has become more important than ever in the biomedical sciences with the advance of high-throughput technology and web-based databases are one of the most efficient available resources to share datasets.
The Institute's 60 brains have long been the leading source of human brain tissue for researchers in biological psychiatry. Whenever you read about a new discovery relating to schizophrenia or bipolar disorder, chances are the Stanley brains were involved. The Institute provide slices of the brains free of charge to scientists who request them, and they've sent out over 200,000 to date.

Until now, if you wanted to find out what these scientists discovered about the brains, you'd have to look up the results in the many hundreds of scientific papers where the various results were published. If you knew where to look, and if you had a lot of time on your hands. The database collates all of the findings. That's a good idea. To ensure that they get all of the results, the Institute have another good idea:
Coded specimens are sent to researchers with the code varying from researcher to researcher to ensure that all studies are blinded. The code is released to the researcher only when the data have been collected and submitted to the Institute.
The data we're provided about the brains is quite exciting, if you like molecules, comprising 1749 markers from 12 different parts of the brain. Markers include levels of proteins, RNA, and the number and shape of various types of cells.

It's easy to use. While waiting for my coffee to brew, I compared the amount of the protein GFAP76 in the frontal cortex between the four groups. There was no significant difference. I guess GFAP76 doesn't cause mental illness - darn. So much for my Nobel Prize winning theory. But I did find that levels of GFAP76 were very strongly correlated with levels of another protein, "phosphirylated" (I think they mean "phosphorylated") PRKCA. You read it here first.

In the paper, Kim and Webster used the Database to find many differences between normal brains and diseased brains, including increased levels of dopamine in schizophrenia, and increased levels of glutamate in depression and bipolar. And decreased GAD67 proteins in the frontal cortex in bipolar and schizophrenia. And decreased reelin mRNA in the frontal cortex and cerebellum in bipolar and schizophrenia. And...

This leaves open the vital questions of what these differences mean, as I have complained before. And the problem with giving everyone in the world the results of 1749 different tests, and letting us cross-correlate them with each other and look for differences between 4 patient groups, is that you're making possible an awful lot of comparisons. With only 15 brains per group, none of the results can be considered anything more than provisional, anyway - what we really need are lots more brains.

But this database is still a welcome move. This kind of data pooling is the only sensible approach to doing modern science, and it's something people are advocating in other fields of neuroscience as well. It just makes sense to share results rather than leaving everyone to do there own thing in near-isolation from each other, now that we have the technology to do so. In fact, I'd say it's a... no-brainer.

ResearchBlogging.orgKim, S., & Webster, M. (2009). The Stanley Neuropathology Consortium Integrative Database: a Novel, Web-Based Tool for Exploring Neuropathological Markers in Psychiatric Disorders and the Biological Processes Associated with Abnormalities of Those Markers Neuropsychopharmacology, 35 (2), 473-482 DOI: 10.1038/npp.2009.151

Two Drugs Are Better Than One?

According to a study just out in the American Journal of Psychiatry, starting depressed people on two antidepressants leads to much better results than starting them on just one - Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder. But how reliable is it?

Currently accepted practice is to prescribe one antidepressant to begin with, and if the patient doesn't feel better after about 6 weeks, to either change to a different antidepressant (switching) or add a second drug while continuing the first (augmentation).

But in clinical trials and also in "real life", the proportion of depressed people who achieve "remission", meaning that they're fully or almost fully recovered, with their first antidepressant is rarely more than 1 in 3. Some antidepressants may be slightly better than others as first-line treatments, but any such differences are small.

Do two mediocre drugs combined add up to one good treatment? In this study, Blier et al. took 105 depressed people and gave them either one antidepressant or two. The one antidepressant was fluoxetine (Prozac) 20mg, and the two was mirtazapine 30mg and either fluoxetine 20mg, venlafaxine 225mg, or buproprion 150mg. The study was double-blind; patients didn't know which drug(s) they were on. There was no placebo group, however.

Mirtazapine (Remeron) is an antidepressant which is commonly used as an add-on treatment in depression, because it can be safely combined with most other drugs. So it makes sense to use mirtazapine in research like this, but take note: this study was "supported by Organon Pharmaceuticals", who make... mirtazapine.

What happened? All three combinations of two antidepressants were equally effective, and all three were considerably better than just Prozac alone, in the initial 6 week phase of the trial. The difference was massive by the standards of antidepressants - about 5 Hamilton scale points, considerably larger than the average benefit of an antidepressant over placebo.

There was also a 6 month follow-up phase to the study in which everyone who had been taking two antidepressants had one of them replaced by placebos, so everyone ended up only taking one drug (either fluoxetine or mirtazapine). Discontinuing one antidepressant seemed to cause relapse in about 40-50% of the people who were taking two, as opposed to a 25% relapse rate in the people who started on just fluoxetine and kept taking it. If you believe it, this is further evidence that two drugs are better than one, although the total sample size was just 66 for this bit, and I'm not sure I do.

What are we to make of all this? This study joins a previous one finding that mirtazapine plus paroxetine is better than either drug alone as a starting treatment. But that paper was also by Blier et al and it was "fully funded by Organon Pharmaceuticals" although apparently "The sponsor had no role in the study design, in the collection and interpretation of the data, in the preparation of this report, and in the decision to publish this manuscript".

Personally, I'm not so much troubled by the industry sponsorship in these studies as I am by the nature of the add-on treatment, mirtazapine. Mirtazapine is an unusual drug, with a pharmacological profile very different to that of most antidepressants. Notably, it's a powerful hypnotic - it makes you sleep - and it increases appetite. Patients on mirtazapine in the present study put on over 2kg in 6 weeks.

Why does this matter? Because the two scales used to rate depression in this study, the Hamilton Scale and the Montgomery-Asberg Scale, both count reduced appetite and sleeplessness as symptoms of depression. If you're on mirtazapine, you're unlikely to have either problem - you'll be more worried about the exact opposite, insatiable hunger and drowsiness. So mirtazapine could reduce your total score on these scales even if it didn't change your mood. I have no idea to what extent this is a factor in these results, but it could be important.

So, are two drugs better than one? Should antidepressants come with a side-order of mirtazapine as standard? Maybe. But it's far from proven.

ResearchBlogging.orgBlier, P., Ward, H., Tremblay, P., Laberge, L., Hebert, C., & Bergeron, R. (2009). Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder: A Double-Blind Randomized Study American Journal of Psychiatry DOI: 10.1176/appi.ajp.2009.09020186

Gamma Knives Out

The Guardian covers contemporary psychosurgery - in their "Life and Style" section, believe it or not -

A radical treatment for Obsessive-compulsive disorder patients
The treatment being "gamma knife" lesions in OCD. Surgeons use a gamma knife to destroy part of the brain by aiming several beams of gamma rays at it from different angles. At the point of the target the beams overlap, and the total radiation level is intense enough to kill cells. Other parts of the brain only get hit by one beam, which is, hopefully, harmless. It's quite a clever technique, although it's not exactly brain surgery. (Sorry...)

Unlike actual surgery, the gamma knife doesn't involve cutting holes in people. This makes it safer, because any neurosurgery carries risks of infection or haemorrhage. But functionally, it's exactly the same as physically removing the tissue with a scalpel. It's hardly "non-invasive", which is what the Guardian call it (twice). Maybe technically, in the sense that it doesn't break the skin, but it does permanently destroy a substantial part of the brain. That's rather more invasive than, say, getting a tattoo, if you ask me.

Lesioning the brain to treat severe OCD has a long history. In the past couple of decades, it's been done on some dozens of patients at a few hospitals such as the Karolinska Institute in Sweden, Brown University in the US, Spain, China and South Korea.

Does it work? Some reports say that about 60% of OCD patients experience a good response others put the rate at more like 40%. So it doesn't work for everyone although given that the patients who get psychosurgery are severely ill and have not benefited from other treatments (medication and therapy), it's not so bad. But it's impossible to know how much of the improvement is a placebo effect, because there's never been a placebo controlled trial of any kind of psychosurgery for OCD, including gamma knife. This is something that the Guardian unfortunately doesn't mention.


Newspapers at the moment are pretty keen on neurosurgery for mental illness. Deep brain stimulation (DBS) has been getting positive coverage for years, and psychosurgery is also becoming popular nowadays. The NYT recently ran a cautious, but generally positive, piece on it.

There seems to be an unwritten rule that every such article has to include a bit reassuring us that today's psychosurgery is Not Like In One Flew Over the Cuckoo's Nest. Hence The Guardian:
The technique certainly could not be further from the brutal lobotomies made famous by Ken Kesey's novel, One Flew Over the Cuckoo's Nest. While the frontal lobotomy essentially destroys part of the brain, Gamma Knife is highly accurate and non-invasive, damaging only a minute area - 100 millimeters square - of brain tissue. It is usually done as an out-patient procedure. Some might experience a mild headache afterwards, but most report no physical problems at all.
And the NYT:

In the early days of psychosurgery doctors published scores of papers detailing how lobotomy relieved symptoms of mental distress. But careful follow-up painted a darker picture: of people who lost motivation, who developed the helpless indifference dramatized by the post-op rebel McMurphy in Ken Kesey’s novel “One Flew Over the Cuckoo’s Nest”... The newer operations pinpoint targets on specific, precisely mapped circuits, whereas the frontal lobotomy amounted to a crude slash into the brain behind the eyes, blindly mangling whatever connections and circuits were in the way.
This old bad, new good message is simplistic and misleading. The old (1930s-1940s) psychosurgery didn't consist of "blindly mangling" the brain. At least at first, it was targeted as precisely as the technology and neuroanatomy at the time allowed. And although some psychosurgeons used it in a cavalier way, there is no doubt that it often seemed to produce dramatic benefits; the contemporary testimonials of patients and their families are proof of that.

Today's surgery allows more accurate (and smaller) lesion placement, thanks to advances in stereotactic techniques and now the gamma knife. But we still have no solid understanding of the brain circuits underlying mental illness. We still don't know why destroying certain frontal white matter pathways in the brain alleviates symptoms. We still don't know why it works in some people and not others.

There's not even much agreement on which parts of the brain to hit; the most popular surgical target for OCD is the anterior limb of the internal capsule (capsulotomy) although cingulotomy has also been used, and for depression there are a handful. To say that "The newer operations pinpoint targets on specific, precisely mapped circuits" is true only in the sense that if a modern surgeon tries to destroy the anterior limb of the internal capsule, they will probably do it.

None of this means that psychosurgery doesn't work. It probably does - or rather, it certainly does, and it's probably not just a placebo. (For one thing the fact that accidental brain damage to the same regions also seems to reduce emotional distress is very promising.) But it's not so different to what was going on in the 1930s. It's still, basically, a stab in the dark.

Link: The Lobotomist and Last Resort are excellent books on the history of psychosurgery.

In the Brain, Acidity Means Anxiety

According to Mormon author and fruit grower "Dr" Robert O. Young, pretty much all diseases are caused by our bodies being too acidic. By adopting an "alkaline lifestyle" to raise your internal pH (lower pH being more acidic), you'll find that

if you maintain the saliva and the urine pH, ideally at 7.2 or above, you will never get sick. That’s right you will NEVER get sick!
Wow. Important aspects of the alkaline lifestyle include eating plenty of the right sort of fruits and vegetables, ideally ones grown by Young, and taking plenty of nutritional supplements. These don't come cheap, but when the payoff is being free of all diseases, who could complain?

Young calls his amazing theory the Alkavorian Approach™, aka the New Biology. Almost everyone else calls it quack medicine and pseudoscience. Because it is quack medicine and pseudoscience. But a paper just published in Cell suggests an interesting role for pH in, of all things, anxiety and panic - The amygdala is a chemosensor that detects carbon dioxide and acidosis to elicit fear behavior.

The authors, Ziemann et al, were interested in a protein called Acid Sensing Ion Channel 1a, ASIC1a, which as the name suggests, is acid-sensitive. Nerve cells expressing ASIC1a are activated when the fluid around them becomes more acidic.

One of the most common causes of acidosis (a fall in body pH) is carbon dioxide, CO2. Breathing is how we get rid of the CO2 produced by our bodies; if breathing is impaired, for example during suffocation, CO2 levels rise, and pH falls as CO2 is converted to carbonic acid in the bloodstream.

In previous work, Ziemann et al found that the amygdala contains lots of ASIC1a. This is intriguing, because the amygdala is a brain region believed to be involved in fear, anxiety and panic, although it has other functions as well. It's long been known that breathing air with added CO2 can trigger anxiety and panic, especially in people vulnerable to panic attacks.

What's unclear is why this happens; various biological and psychological theories have been proposed. Ziemann et al set out to test the idea that ASIC1a in the amygdala mediates anxiety caused by CO2.

In a number of experiments they showed that mice genetically engineered have no ASIC1a (knockouts) were resistant to the anxiety-causing effects of air containing 10% or 20% CO2. Also, unlike normal mice, the knockouts were happy to enter a box with high CO2 levels - normal mice hated it. Injections of a weakly acidic liquid directly into the amygdala caused anxiety in normal mice, but not in the knockouts.

Most interestingly, they found that knockout mice could be made to fear CO2 by giving them ASIC1a in the amygdala. Knockouts injected in the amygdala with a virus containing ASIC1a DNA, which caused their cells to start producing the protein, showed anxiety (freezing behaviour) when breathing CO2. But it only worked if the virus was injected into the amygdala, not nearby regions.

This is a nice series of experiments which shows convincingly that ASIC1a mediates acidosis-related anxiety, at least in mice. What's most interesting however is that it also seems to involved in other kinds of anxiety and fear. The ASIC1a knockout mice were slightly less anxious in general; injections of an alkaline solution prevented CO2-related anxiety, but also reduced anxiety caused by other scary things, such as the smell of a cat.

The authors conclude by proposing that amygdala pH might be involved in fear more generally
Thus, we speculate that when fear-evoking stimuli activate the amygdala, its pH may fall. For example, synaptic vesicles release protons, and intense neural activity is known to lower pH.
But this is, as they say, speculation. The link between CO2, pH and panic attacks seems more solid. As the authors of another recent paper put it
We propose that the shared characteristics of CO2/H+ sensing neurons overlap to a point where threatening disturbances in brain pH homeostasis, such as those produced by CO2 inhalations, elicit a primal emotion that can range from breathlessness to panic.
ResearchBlogging.orgZiemann, A., Allen, J., Dahdaleh, N., Drebot, I., Coryell, M., Wunsch, A., Lynch, C., Faraci, F., Howard III, M., & Welsh, M. (2009). The Amygdala Is a Chemosensor that Detects Carbon Dioxide and Acidosis to Elicit Fear Behavior Cell, 139 (5), 1012-1021 DOI: 10.1016/j.cell.2009.10.029

That Sinking Feeling?

Sinking and Swimming is a paper just out from the Young Foundation, a British think-tank. It "explores how psychological and material needs are being met and unmet in Britain." I'm not sure how useful their broad concept of "unmet needs" is, but there's some rather interesting data in this report.

On page 238, and prominently in the executive summary, we find the following terrifying graph, which comes with warnings like "anxiety and depression looks set to double during the course of a single generation..."

The % of the population self-reporting suffering from depression or anxiety seems to have been consistently rising since 1990, from less than 6% to almost 10% today. And the line continues ever upwards. Eeek!

Is Britain really becoming more depressed and anxious? No, and that's what makes this graph terrifying. According to the large government Adult Psychiatric Morbidity Survey, the prevalence of self-reported depression and anxiety symptoms rose slightly from 1993 to 2000 (15.5% to 17.5%) and then stayed level up to 2007 (17.6%). Not very scary. Even the Young Foundation note (on page 80) that when you look at "well-being"

analysis of the English health survey that uses a variation of GHQ [General Health Questionnaire] suggested that the proportion of the working age population with poor psychological well-being decreased from 17% in 1997 to 13% in 2006.
On that measure, we're getting happier. And the rate of new diagnoses of clinical depression fell over the past decade.

So what about that ominous line? Well, that graph was based on "self-reported anxiety or depression", but in a specific sense. People were not reporting feeling scared or unhappy (see above for the data on that), but rather, reporting having anxiety or depression as medical disorders. Curiously the % of people reporting having every other sort of health problems (except with vision) increased from 1991 to 2007 as well:

What seems to be happening is that British people are becoming more willing to label our problems as medical illnesses, although in fact our mental health has not changed much over the past two decades, and may even have improved slightly. This is what's terrifying, because medicalizing emotional issues is a bad idea.

Mental illness does exist, and medicine can help treat it, but medicine can't resolve non-medical problems even if they're labelled as illnesses. Antidepressants, for example, are (imperfectly) effective for severe clinical depression but probably not for "mild depression"; much of what is labelled "mild depression" is probably not, in any meaningful sense, an illness.

Why does this matter? Drugs have side effects, and psychotherapy is expensive. The cost-benefit profile of any treatment is obviously negative when there are no benefits because the treatment is being used inappropriately. My biggest concern, though, is that if someone is unhappy because of tensions in their marriage or because they're in the wrong job, they don't need treatment, they need to do something about it. Labelling a problem as an illness and treating it medically may, in itself, make that problem harder to overcome.


Psychiatrist, Drug Thyself

Psychiatrists give their patients all kinds of drugs, but in most cases, they do so without ever taking any themselves. Some French psychiatrists found an excuse to try out some drugs in the name of science, and the results are published in a paper just out - Besnier et al's Effects of paroxetine on emotional functioning and treatment awareness.

Thirty healthy psychiatrists and clinical psychologists took paroxetine 20mg per day, or placebo pills, for 4 weeks. Paroxetine (Paxil, Seroxat) is a popular SSRI antidepressant - popular with doctors, at least. It has a bad reputation amongst users as causing serious withdrawl symptoms, even compared to other SSRIs. These psychiatrists decided to wean themselves off with a week at a reduced dose of 10mg before stopping completely - after just one month on it! Make of that what you will.

Anyway, what happened? The participants experienced no changes in mood or anxiety, although since they weren't depressed or anxious to begin with, this is not surprising. However, the people taking paroxetine did report reduced "Internal Emotional Experience" as measured with the Emotional State Questionnaire (designed by the same people who ran this study.) That means they were less likely to answer yes to questions like “Do you feel anger when faced with a familiar face with expressed anger?”

This sounds as though they experienced the "emotional blunting" reported by some people who take SSRIs, although it's not clear what exactly this questionnaire is measuring, or how powerful the effect was. The paroxetine group also reported feeling sedated and suffered many more side effects - 70% of participants presented with an adverse event for more than 3 weeks, vs 20% of placebo.

Most described adverse events were psychiatric (sleepiness disorders, libido decreased), gastrointestinal (nausea, diarrhea), or neurological signs (headache).
There's a twist, though, in that while 20 of the subjects got placebo or paroxetine in a double-blind manner (10 each), the other 10 got paroxetine unblinded, i.e. they knew they were not going to get placebo. Strangely, the unblinded group experienced much weaker effects than the double-blind paroxetine group, including many fewer side effects. What's up with that? It's hard to say. It doesn't make much sense. To be honest, with just 10 people in each group, any or all of these results could be random chance anyway.

Still, I do like the idea of psychiatrists self-experimenting. Sadly we're not told whether they were more or less likely to prescribe paroxetine after taking it themselves! Still, I have a bit of anecdotal evidence here. I was talking to a French psychiatrist a while ago who said he'd self-prescribed the SSRI antidepressant citalopram and thought it was brilliant. But one day he accidentally picked up a box of chlorpromazine instead (they were next to each other on the shelf) and that wasn't much fun at all...

Freudian psychoanalysis requires trainee therapists to undergo a full course of therapy themselves before they get to inflict it on their patients. Maybe psychiatrists should have to take courses of antidepressants and antipsychotics as part of their training? Or as the psychopathic bounty hunter said to the doctor in Joss Whedon's Firefly -
Jubal Early: You ever been shot?
Dr Simon Tam
: No.
Jubal Early
: You oughta be shot. Or stabbed. Lose a leg. To be a surgeon, you know? Know what kind of pain you're dealing with. They make psychiatrists get psychoanalyzed before they can get certified, but they don't make a surgeon get cut on. That seem right to you?
- Firefly
ResearchBlogging.orgBesnier N, Cassé-Perrot C, Jouve E, Nguyen N, Lançon C, Falissard B, & Blin O (2009). Effects of paroxetine on emotional functioning and treatment awareness: a 4-week randomized placebo-controlled study in healthy clinicians. Psychopharmacology PMID: 19826792

Big Pharma Drama in Iceland

Icelandic academic and Neuroskeptic reader Steindór J. Erlingsson reports that thanks to his efforts, pharmaceutical company GlaxoSmithKlein (GSK) has stopped distributing a booklet promoting the monoamine hypothesis of depression to pharmacies and doctors offices in Iceland.

His report is here, and it has links to more details on the story, although these are in Icelandic, a language I'm unfortunately not familiar with. In a nutshell, Erlingsson says he spoke to the Icelandic Medical Director of Health who, after some back-and-forth and consultations with psychiatrists, contacted GSK.

On September 29th GSK announced that they

have received information that its information booklet on depression needs to be improved. The company views favorably well argued suggestions and as a result it is going to review the booklet.
They went on to say that the booklet, which had been around since 1999, should no longer be distributed. According to Erlingsson, the booklet made three claims:
1. An imbalance in the neurotransmitter serotonin causes depression. 2. SSRIs treat depression by correcting the serotonin imbalance. 3. Psychological treatment is ineffective in treating the serotonin imbalance.
Coincidentally, GSK are the manufacturers of paroxetine (Paxil, Seroxat), one of the best-selling SSRIs. Iceland, like most countries (except the US and New Zealand), bans direct-to-consumer advertising for drugs, but this kind of thing is not covered by such laws.

Personally I believe that serotonin probably is involved in some cases of depression. My views on the serotonin hypothesis of depression are therefore more favorable than those of many critics for whom the whole idea is a myth. But even so, I'm happy that to hear that this booklet has been withdrawn. Drug companies have no business promoting the serotonin hypothesis to the public.

First off, because it's controversial science. There's no "smoking gun" proof linking serotonin to depression. There's a lot of circumstantial evidence, but we don't really know how antidepressants work, or indeed how well they work, at all. For once, we should be "Teaching the Controversy". Most of the time when people say that, they're wrong, because they're talking about science which is rock solid, like the theory of evolution. The monoamine theory, however actually is controversial, which is why there are articles in major scientific journals criticizing it and others defending it.

Second, because the monoamine theory is certainly not true in any simple sense. Low serotonin levels cannot be the sole cause of depression because you can temporarily deplete someone's serotonin with a technique called tryptophan depletion and for most people, this does nothing at all to their mood. On the other hand about 50% of people who have suffered from depression in the past do get depressed again after tryptophan depletion, which is why I think there is some truth in the serotonin theory, but this shows that it's not a straightforward picture.

Third, the idea that only drugs can correct the "chemical imbalance" and psychotherapy can't is simply wrong. I don't know what the wording of GSK's booklet was, but from Erlingsson's summary, it sounds like it was giving people medical advice - you won't benefit from therapy - via leaflet, which is very irresponsible. Only a clinician with personal experience of an individual patient can say what treatment is best for them. Some people benefit from therapy, others do well on medication, and some people get better with no treatment at all. It sounds like GSK is behaving just as Oliver James did when he used the Guardian to recommend Freudian psychoanalysis over drugs and other kinds of therapy for postnatal depression. They're both wrong.

On the other hand, information leaflets telling people about depression and encouraging sufferers to seek professional help sound like a great idea to me, because many people with depression go undiagnosed and untreated and that's a real tragedy. But drug companies are unlikely to be the best people to provide such information.

The Acting Brain!

The BBC promises us a look

Inside an actor's brain during a performance
Actress Fiona Shaw had an fMRI scan. Parts of her brain were more active while she was reading a poem by T. S. Eliot featuring dialogue than when she was merely counting. So what?

The fact that different parts of Shaw's brain were active whilst reading Eliot than when counting out loud is unsurprising. Different parts of the brain do different things - this is not news - and reading poetry is certainly very different from counting. This doesn't mean that "Fiona Shaw's brain appears to be adapted to acting", as the article says. If your brain was adapted to acting it would look like this:

All dressed up, skull in hand, ready to portray Hamlet - "Alas, poor Yorick..." Actually, brains generally do carry skulls around with them, so maybe there's something in it.

In fact, Shaw's brain presumably is adapted to acting - she's an actress. If you're able to do something, your brain must be able to do it, because you are your brain after all. In just the same way, my brain is adapted to being a neuroscientist and Barack Obama's brain is adapted to being President. This is not news either. However, the fMRI scan doesn't tell us anything about how Shaw's brain is adapted to acting.

We are told which areas of Shaw's brain lit up while she was reading poetry, and what this means -
Towards the front of the brain there is a part associated with "higher order" control of behaviour. Towards the top of the brain is a section which controls the movement of the hands and arms - even though she wasn't waving her arms about, she was apparently thinking about doing so.

And towards the back of the head is an area associated with complex visual imagery, even though she wasn't performing a complex visual task. The scan backs up work with professional impressionists, whose brains also conjure up visual images of the people they're imitating.

All very plausible - this is a nice convincing story to explain what these brain areas are doing while reading a passage of poetry in which people are talking to each other. It makes perfect sense. But the problem is, so would anything else.

Suppose that Shaw's hippocampus had lit up as well. That's involved in memory. She's remembering having read T. S. Eliot before! What if she's never read him? Well, the hippocampus must be forming a new memory. Her medial prefrontal cortex is activating? Clearly, that's the emotional impact of reading this masterpiece of modernist poetry. And so on. These areas did not, in fact, light up, but if they had, it would have made perfect sense too.

The point is that we all know what kinds of things go on in our heads while reading poetry - visual imagery, memories, emotions etc. And each brain region has numerous functions, many of which are sufficiently vague ("social cognition", "emotion") to cover almost anything, especially if you allow that a brain area can activate whenever someone is merely thinking about doing something rather than actually doing it. So whatever blobs appear on the brain, it's easy to invent a story linking these to the whatever task is going on.

It's like astrology. Astrological "readings" always seem accurate because they can be made to fit anyone. Actress Fiona Shaw is a Leo and Leo's have "a flair for drama. In fact, many Leos are attracted to the theatre, the performing arts and public relations". It fits so well! Actually, I made a mistake with my dates, she's a Libra. No problem, "Libra is among the most sociable of the signs...drawn toward creative endeavours." - obviously a born actress. And so on. (She's actually a Cancer.)

Perhaps it's unfair to criticize this experiment. It was a demonstration of fMRI technology for the "Wellcome Collection's new exhibition on identity". The scan was for educational purposes only, it wasn't meant to be proper science.

The problem is that a lot of what is meant to be rigorous science consists of this kind of thing. The Discussion sections of many fMRI papers are full of stories linking whatever brain regions happened to be activated to whatever the task in the experiment was. Most fMRI studies today are more sophisticated than simply scanning normal people doing some task, but the same kind of post-hoc storytelling can be applied to areas of the brain that light up differently in mentally ill people compared to healthy people, or areas that light up in response to a drug, etc.

Of course this doesn't mean that these stories are false. Shaw's visual cortex probably did activate because she was mentally imagining the people and the scene she was reading about - that explanation's good enough for me. The point, though, is that we don't really know, because whatever the fMRI data was, we could have made an equally convincing story having seen it.

What we need are hypotheses made up before doing the experiment, which can then be tested and verified, or falsified, on the basis of the data. As I wrote a couple of months back:
Much of today's neuroimaging research doesn't involve testable theories - it is merely the exploratory search for neural differences between two groups. Neuroimaging technology is powerful, and more advanced techniques are always being developed... the scope for finding differences between groups is enormous and growing.

Exploratory work can be useful as a starting point, but at least in my opinion, there is too much of it. If you want to understand the brain you need a theory sooner or later. That's what science is about.

Mental Illness vs. Suicide

Do countries with more mental illness have more suicides?

At first glance,
it seems as though the answer must be "yes". Although not all suicides are related to mental illness, unsurprisingly people with mental illness do have a much higher suicide rate than people without. So, all other things being equal, the rate of mental illness in a country should correlate with the suicide rate. Of course, all other things are not equal, and other factors might come into play such as the quality of mental health services. But it still seems as though there should be a correlation, albeit not a perfect one, between mental illness and suicide.

I decided to see whether or not there is such a correlation. The World Health Organization (WHO)
provides the relevant data here. There have only ever been three studies attempting to measure rates of common mental illnesses internationally (1,2,3), and all three were run by the WHO. The WHO also collates national suicide rates (here) for most countries, although a few are missing. No-one seems to have published anything looking for a correlation between these two sets of numbers of before, or if they did, I've failed to find it.

So what's the story? Take a look -

In short, there's no correlation. The Pearson correlation (unweighted) r = 0.102, which is extremely low. As you can see, both mental illness and suicide rates vary greatly around the world, but there's no relationship. Japan has the second highest suicide rate, but one of the lowest rates of mental illnesses. The USA has the highest rate of mental illness, but a fairly low suicide rate. Brazil has the second highest level of mental illness but the second lowest occurrence of suicide.


Some technical notes: Two of the three surveys, the ICPE (2000) and the WMHS (2004), sampled the whole population of each country. The other one, which was also the earliest, the PPGHC (1993), surveyed people attending family doctors. Because this is a slightly different approach, I used the ICPE and the WMHS for the plot above, although the results from the PPGHC are very similar (see below).

The ICPE sampled 7 countries and the WMHS sampled 14, but 4 countries were included in both surveys, so there's a total of 17 countries. I've used the mean of the ICPE and the WMHS for those 4 countries where we have data from both, for the rest I've used whichever is available. For the suicide rates, the WHO gives data for various different years, so I've used 2002, or the nearest available year, since this is between 2000 and 2004. For two countries, Lebanon and Nigeria, the WHO do not report suicide rates. For China, rates of mental illness are given in both Beijing and Shanghai.

The studies used structured diagnostic interviews to try to measure the percentage of people suffering from mental illness in the 12 months before the interview. As I've said previously, this -
attempts to study a random sample of the population of a certain country. In order to establish whether each person is mentally ill or not, they use structured diagnostic interviews. These consists in asking the subject a fixed ("structured") series of questions, and declaring them to have a certain mental disorder if they answer "Yes" to a given number of them.
In this case the structured question interview was called the CIDI and it used DSM-IV criteria. You can check it out here. Example question:
You mentioned having periods that lasted several days or longer when you felt sad, empty, or depressed most of the day. During episodes of this sort, did you ever feel discouraged about how things were going in your life? (YES, NO, DON’T KNOW, REFUSED)


The rates from the population surveys (ICPE & WMHS) don't correlate with suicide but they do correlate with the rates from the PPGHC survey of people attending family doctors. The association here is very strong, with a correlation r = 0.693. The only outlier is the US. This is despite the fact that a decade elapsed between the first survey (1993) and the other two (2000, 2004).

This is important because it shows that the mental illness surveys are measuring something about these countries, something which is stable over time. They're not just producing random junk results. But whatever they're measuring, it's not related to suicide.


What does this mean? You leave a comment and tell me. But here's my take.
I've often expressed skepticism of population surveys and their (very high) estimates of mental illness, and of the dubious political conclusions certain people have tried to draw from them, but even so, I was surprised to find no correlation at all with suicide. I'd say that any meaningful measure of mental illness should correlate with suicide. These surveys, using the CIDI, don't, so to me they're not meaningful.

One thing to bear in mind about these numbers is that they deal with "common" mental illnesses like depression, substance abuse and anxiety. They leave out the most severe disorders such as schizophrenia. Also, people in psychiatric hospitals, in prison, and the homeless, will not have been included in the studies because they sample "households". That could be why there's no association with suicide, but if so then these surveys are missing a very important aspect of mental health.

The surveys do seem to measure something, but I don't think it has much to do with mental illness. This is just a guess but I suspect they're measuring willingness to talk about your emotional life to strangers. At least stereotypically, the Chinese and the Japanese are known as more reserved in this regard than Brazilians and Americans.
So it's no surprise that when you ask people a load of personal questions, the "rates of mental illness" seem to be lower in Japan than in America. This doesn't mean Americans are really more ill, just more open.

I've been talking about surveys looking at differences between countries, but if these are flawed, then so are surveys looking at just one country.
For example, many studies have looked at mental illness in the USA using similar methods to these. But can we trust these methods bearing in mind that if you ask the same questions in, say, Belgium you get less than half the estimated rate despite it having double the number of suicides? Taken to its logical conclusion, maybe we know little about the prevalence of "common mental illness" anywhere.

ResearchBlogging.orgSartorius N, Ustün TB, Costa e Silva JA, Goldberg D, Lecrubier Y, Ormel J, Von Korff M, & Wittchen HU (1993). An international study of psychological problems in primary care. Preliminary report from the World Health Organization Collaborative Project on 'Psychological Problems in General Health Care'. Archives of general psychiatry, 50 (10), 819-24 PMID: 8215805

WHO (2000). Cross-national comparisons of the prevalences and correlates of mental disorders. WHO International Consortium in Psychiatric Epidemiology. Bulletin of the World Health Organization, 78 (4), 413-26 PMID: 10885160

Demyttenaere K, & et Al (2004). Prevalence, severity, and unmet need for treatment of mental disorders in the World Health Organization World Mental Health Surveys. JAMA, 291 (21), 2581-90 PMID: 15173149

Another Drug to Treat Drug Addiction

Today I was going to blog this paper, which says that you can predict which kids will grow up and be criminals by measuring their Pavlovian fear conditioning at age 8. In Mauritius. But The Last Psychiatrist already said everything I was going to.

Luckily, there's another article in the American Journal of Psychiatry about crime in a tropical country for me to write about - Randomized, Double-Blind, Placebo-Controlled Trial of Vigabatrin for the Treatment of Cocaine Dependence in Mexican Parolees.

The study found that a drug called vigabatrin helped Mexican cocaine users to stay clean. The addicts were all on parole from jail. They "were poor and unemployed or underemployed, and none had permanent telephone numbers", had a mean age of 30, and had been using cocaine, including crack, for 9 years on average. A difficult population, then.

They were given either vigabatrin, or placebo, every morning for 7 weeks, and their cocaine use was measured with urine samples twice a week. If they managed to stay clean for 3 straight weeks, that was counted as successful treatment. What happened? In the placebo group, almost no-one managed to get clean - just 4 out of 53 (7.5%). But in the people on vigabatrin, 14 out of 50 made it (28%):

Now there's two ways of describing this result. You could say, as the authors did, that "nearly four times as many subjects taking vigabatrin achieved full end-of-trial abstinence", which makes it sound amazing. Four times as many, woo! Or you could say that only 1 in 5 people were helped by the drug - not so good. But hey, it's still a result. And it's a lot more impressive than the "cocaine vaccine".

Interestingly, many of the cocaine addicts were alcoholics too, and in the vigabatrin group 10 of them (43%) also achieved abstinence from alcohol, vs just 1 (6%) in the placebo group.

What's vigabatrin? It's an anticonvulsant used in some countries - including Mexico but not the U.S. - to treat severe forms of epilepsy. Like most anticonvulsants, it works on the neurotransmitter GABA which inhibits neural firing; specifically, vigabatrin prevents GABA from being broken down by an enzyme in the brain. In laboratory experiments, it stops rats and mice from enjoying the effects of cocaine, probably because it blocks the ability of cocaine to increase dopamine levels.

That all sounds promising, but there's a catch. Vigabatrin causes "a tardive peripheral visual field defect that is typically asymptomatic and neither progresses nor resolves upon treatment cessation" as the paper tells us. In other words, prolonged use causes permanent loss of peripheral vision, i.e. "tunnel vision". This can be severe in some cases. They tested for it, and it didn't happen to anyone in this study, but that's probably because it was a short trial and the cumulative total dose was about 10% of the amount that's thought to cause problems: 130g vs. 1,500g. Long-term treatment might be more of an issue.

So why use vigabatrin, when there are plenty of other anticonvulsants that don't permanently damage your eyes? This is the first placebo-controlled trial of vigabatrin but there have been many trials of other anticonvulsants for cocaine dependence and they generally didn't work. So maybe vigabatrin is unique and more effective than other drugs of its kind. Only time, and bigger trials, will tell.

ResearchBlogging.orgBrodie, J., Case, B., Figueroa, E., Dewey, S., Robinson, J., Wanderling, J., & Laska, E. (2009). Randomized, Double-Blind, Placebo-Controlled Trial of Vigabatrin for the Treatment of Cocaine Dependence in Mexican Parolees American Journal of Psychiatry, 166 (11), 1269-1277 DOI: 10.1176/appi.ajp.2009.08121811

One Pill Makes Your Libido Larger

It's every man's dream - a pill to make women want more sex. According to Boehringer Pharmaceuticals, that dream could be a reality in a few years, in the form of the strangely-named flibanserin. But is it the latest wonder-drug or just a glorified sleeping pill? Read on.

Flibanserin was originally developed as an antidepressant, but in clinical trials against depression it reportedly failed to perform better than placebo. The standard for getting approved as an antidepressant is low, so this is quite an achievement.

The BBC today described flibanserin as the "Female Viagra", which is rather confusing, because it's meant to increase sexual desire, which is one thing Viagra (sidenafil) doesn't do. The reason for the Female Viagra headline is that, as Professor John Thorp says:

"It's essentially a Viagra-like drug for women in that diminished desire or libido is the most common feminine sexual problem, like erectile dysfunction is in men"
Yes, one in ten women suffer apparently from "Hypoactive Sexual Desire Disorder" (HSDD) as Boehringer Pharmaceuticals helpfully informs us. And “As many as two out of every 10 women describe some degree of decreased sexual desire" according to the unfortunately named Dr Charles de Wet, Boehringer medical director for the UK.

HSDD is a diagnosis in the DSM-IV, the American Psychiatric Association's listing of psychiatric illnesses, and it's been recognised as a disorder since 1980. It is not, however, a very popular diagnosis yet. There are only 60,000 Google hits for it, as opposed to 1,600,000 for "major depression" and, er, 90,000 for "neuroskeptic". Odd for a disorder apparently plaguing at least 10% of women.

Indeed, some people say that it's no more than a label invented by psychiatrists who didn't understand women and then promoted by drug companies in order to sell drugs. This is almost certainly true, but it's also a bit simplistic, because there are people who perceive themselves as suffering from low libido, and if flibanserin really helps them, that's surely a good thing.

How is flibanserin supposed to work? According to a paper on the Pharmacology of Flibanserin, it's a serotonin receptor 5HT1A agonist and a 5HT2A antagonist. This makes it a kind of cross between the antidepressants nefazadone and buspirone. Neither of these are widely used as antidepressants because they're not considered highly effective. Flibanserin is also a weak dopamine D4 receptor partial agonist. This might underlie its aphrodisiac properties, because drugs which increase dopamine levels are known to enhance motivation and libido (or indeed cause problematic hypersexuality.) In rats and mice, flibanserin has sedative effects and enhances the effects of other sedatives. It also has antidepressant-like effects in some tests but not all. Drug geeks can click the image on the left for more details.


Now for the big question - does it actually work? Well, there have been no published clinical trials yet. At all. The trials in depression, where it failed to work, have never been published. Hmm. However, four trials in "Hypoactive Sexual Desire Disorder" were recently completed and the results were presented yesterday at a sexual medicine conference in Europe (ESSM) in the form of three posters (1,2,3). The trials were known as - groan - VIOLET, ORCHID, DAISY and DAHLIA. I probably don't have to tell you that they were all funded by Boehringer Pharmaceuticals.

The main poster is Efficacy of flibanserin 100 mg qhs as a potential treatment for Hypoactive Sexual Desire Disorder in premenopausal women which pools the data from three trials with a total of about 1,400 women. They found that taking flibanserin 100 mg every night had small beneficial effects. Relative to placebo, it increased the number of "satisfying sexual encounters" by 0.7 per month. It also improved scores on questionnaire measures of sexual function, a bit.

In any trial like this you have to ask whether there is result cherry-picking going on. Maybe they asked dozens of questions about the women's sex lives, and they're only telling us about the minority where the drug seemed to work? People often do that but in this case, the Clinical Trials Register suggests there was no funny business of that kind. It also shows that there have been no trials using 100mg which weren't included in the poster, so the trials themselves weren't cherry picked either. That's reassuring. But it looks like the effects were only significant when all three trials were pooled - one poster shows the results of the ORCHID trial alone, and most were non-significant.

What about the side effects? There's a whole poster about them. 100 mg flibanserin nightly caused 14% of patients to drop out due to side effects, vs 7% in the placebo group - so an extra 7% decided it wasn't worth it. It caused dizziness, nausea, fatigue, somnolence - and bizarrely, also insomnia. Notably, 50mg daily was much worse than 100 mg nightly, which suggests that taking this at night, rather than in the morning, is a good idea. But given what it is meant to treat, you'd want to do that anyway, right?

But this leads onto my biggest problem with these findings. It's obvious from the side effects data that this drug is a sedative - it makes you tired and sleepy. The animal data confirm this. It's much more likely to put you to sleep than it is to make you enjoy sex in any given month. Off the top of my head, I suspect its sedative properties are a result of its 5HT2A antagonism.

Any sedative can increase sexual desire, as anyone who has ever been to a bar will know. So whether this drug actually has an aphrodisiac effect, as opposed to just being a sleeping pill, is anyone's guess. To find out, you'd need to compare it to a sleeping pill, say, Valium. Or a couple of glasses of wine. Until someone does that, we don't know if this drug is destined to be the next big thing or a big disappointment.

Edit: Just noticed that Dr Petra Boynton has a fantastic post about the background to flibanserin and the manufacturer's apparent attempt to recruit her to write about HSDD.


Borsini F, Evans K, Jason K, Rohde F, Alexander B, Pollentier S (2002). Pharmacology of flibanserin. CNS drug reviews, 8 (2), 117-42 PMID: 12177684

B-Movie Medicine

We all know about movies that are so bad, they're good. But could the same thing apply to doctors?

As I described last week, Desiree Jennings is a young woman from Virginia who developed horrible symptoms, including muscle spasms and convulsions, after getting a flu vaccine. It looked a bit like a form of brain damage called dystonia.

Numerous neurologists concluded that her illness was mostly or entirely psychogenic. A certain Dr Rashid Buttar, however, said that she was suffering from neurological damage caused by toxins in the flu vaccine.

Buttar gave her chelation therapy to flush the toxins out. Within 15 minutes, she was cured. Biologically speaking, this is ludicrous. It's flat-out impossible that chelation could reverse brain damage in 15 minutes, even if Jennings did have brain damage in the first place.

But Buttar's treatment worked, amazingly well by all accounts. This is not surprising, because the illness was psychological in nature, and Dr Buttar's treatment was, psychologically, very effective. Jennings was admitted to Dr Buttar's private clinic; she had IV lines put in to her arm; Dr Buttar attached the chelation treatment to the IV drip and, in a textbook example of how to produce a placebo effect:

I told her "Now the magic should start", prepared her for what I expected to happen. (interview with Dr Buttar, 05:30 onwards)
The magic did indeed happen, precisely because Dr Buttar convinced Jennings that it would.


What would have happened to Jennings if there were no Dr Buttars in the world? Her doctors would have run scans and tests to check if Jennings had any neurological damage. The results would have been normal. Jennings would probably have interpreted this as "We don't know what's wrong with you", although experts would have suspected that the symptoms were most likely psychogenic.

At some point, someone would have had to raise that possibility with her. But the point about psychogenic illness is that it's not "faking", "acting" or "made up" - the patient believes they are ill. The symptoms don't feel psychogenic. This is why people often interpret the suggestion that symptoms are psychogenic as saying "you're not really ill" and hence "you're either lying, or crazy". Of course, patients suffering from psychogenic illness are neither, and they know it.

So, without complementary and alternative medicine, Jennings might have ended up believing herself to be suffering from an illness so obscure that doctors were unable to diagnose it, and hence, unable to cure it. A hopeless situation. A worse thing for someone with psychogenic symptoms to believe is hard to imagine.

Dr Buttar's treatment was psychologically very powerful - precisely because he believed in it, so he was able to convince Jennings to believe in it. A doctor who realized that Jennings' symptoms were psychogenic would have found it much harder to achieve the same result. In order to do so, they would have to lie to her, by pretending to believe in a treatment which they knew was just a placebo. This is hard - the doctor would need to be an excellent actor as well as a medic - not to mention ethically tricky.

Interestingly, 100 years ago, this problem wouldn't have arisen. Doctors knew much less about diagnosis and there were few laboratory tests or scans in those days, so there was usually no way to prove that some symptoms were organic and others were psychogenic. Everyone got the same treatment. Of course, the treatments back then were less good at treating organic illnesses, but that wouldn't necessarily have made them any worse as placebos. Ironically, as mainstream medicine gets better and better at diagnosing and treating disease, it may be getting worse at dealing with psychogenic symptoms.


More on Medical Marijuana

Previously I wrote about a small study finding that smoked marijuana helps with HIV-related pain. In the last month, two more clinical trials of medical marijuana - or rather, marijuana-based drugs - for pain have come out.

First, the good news. Johnson et al tested a mouth spray containing the two major psychoactive chemicals in marijuana, THC and CBD. Their patients were all suffering from terminal cancer, which believe it or not, is quite painful. Almost all of the subjects were already taking high doses of strong opiate painkillers: a mean of 270 mg morphine or equivalent each day, which is enough to kill someone without a tolerance. (A couple of them were on an eye-watering 6 grams daily). Yet they were still in pain.

Patients were allowed to use the cannabinoid spray as often as they wanted for 2 weeks. Lo and behold, the THC/CBD spray was more effective than an inactive placebo spray at relieving pain. The effect was modest, but statistically significant, and given what these people were going through I'm sure they were glad of even "modest" effects. A third group got a spray containing only THC, and this was less effective than the combined THC/CBD - on most measures, it was no better than placebo. THC is often thought of as the single "active ingredient" in marijuana, but this suggests that there's more to it than that. This was a relatively large study - 177 patients in total - so the results are pretty convincing, although you should know that it was funded and sponsored by GW Pharma, whose "vision is to the global leader in prescription cannabinoid medicines". Hmm.

The other trial was less promising, although it was in a completely different group - patients with painful diabetic neuropathy. The people in this study were in pain despite taking tricyclic antidepressants, which, curiously, are quite good at relieving neuropathic pain. Again, the treatment was a combined CBD/THC spray, and this trial for lasted 12 weeks. The active spray was no more effective than the placebo spray this time around - both groups improved a lot. This was a small trial (just 29 patients), so it might just have not been big enough to detect any effect. Also, this one wasn't funded by a pharmaceutical company.

Overall, this is further evidence that marijuana-based drugs can treat some kinds of pain, although maybe not all of them. I have to say, though, that I'm not sure that we needed a placebo-controlled trial to tell us that terminal cancer patients can benefit from medical marijuana. If someone's dying from cancer, I say let them use whatever the hell they want, if they find it helps them. Dying patients used to be given something called a Brompton cocktail, a mixture of drugs that would make Keith Richards jealous:  heroin, cocaine, marijuana, chloroform, and gin, in the most popular variant.

And why not? There were no placebo-controlled trials proving that it worked, but it seemed to help, and even if it was just a placebo (which seems unlikely), placebo pain relief is still pain relief. I'm not saying that these kinds of trials aren't valuable, but I don't think we should demand cast-iron proof that medical marijuana works before making it available to people who are suffering. People are suffering now, and trials take time.

Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, & Fallon MT (2009). Multicenter, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group Study of the Efficacy, Safety, and Tolerability of THC:CBD Extract and THC Extract in Patients With Intractable Cancer-Related Pain. Journal of pain and symptom management PMID: 19896326

Selvarajah D, Gandhi R, Emery CJ, & Tesfaye S (2009). A Randomised Placebo Controlled Double Blind Clinical Trial of Cannabis Based Medicinal Product (Sativex) in Painful Diabetic Neuropathy: Depression is a Major Confounding Factor. Diabetes care PMID: 19808912

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