When I was 12-years old I had a run of history and science projects that absorbed all my interest and exhausted the resources of my local library. Inexplicably, I was granted in-library reading privileges at the University Library. I was free to consult not only books but academic journals and popular reviews. For the first time, I saw publications that I had only read about: London Review of Books, Time Magazine, Paris Match, The Economist, New Yorker. I was overwhelmed by the glamour and gravitas of these periodicals: the smell and weight of the paper stock, the photo-journalism and, above all, the quality of the writing and editing.
I lionised the writers, editors, photographers and contributors who made these periodicals possible; they were portals into the worlds of literature, politics, science and the splendours of Nature. I met people whom I now know to be professors reading these reviews, they would sometimes talk to me about the stories. One remarkable man would hold small groups spellbound with his effortless charm, erudition and impromptu seminars: he had a smudged mark on his arm and I remember the shock of learning that it was his concentration camp number. I conflated the periodicals and the people I met when poring over them: to me, they were chroniclers of contemporary history, polymaths of unimpeachable integrity, acting as Virgils to tentative, unformed Dantes who knew nothing about the worlds of knowledge and politics that they were entering.
I’ve lost my trust in most media and considerably modified my opinion of academics and academia but I retain an instinctive affection and respect for these periodicals. So, I can’t begin to describe my disappointment that The Economist somehow veered from its olympian standards and published a piece of such gob-smacking credulity that I was left waiting for the volte-face punchline that didn’t come. More extraordinary is the fact that The Economist links to Food for the Brain (FFTB) and lends its gravitas to that organisation by carrying this article about its recent conference (you may recall the awfulness of the lamentable Food for the Brain Child Survey 2007, details in further reading).
Treatment on a plate displays shoddy scholarship that is a strong warning sign that there is either a substantial misunderstanding or an undisclosed conflict of interest: this is not typical of The Economist,[a] which makes this article all the more dispiriting.
Treatment on a plate opens with a trite, reductionist description of addiction as distorted levels of neurotransmitters which seems very familiar.[b]
Some drugs mimic [the actions of neurotransmitters]. Others enhance them. Either way, the body tends, as a result, to give up making them. At that point the person needs the drug as a substitute for the missing transmitter. In other words, he is an addict.
Unfortunately, this improved understanding of the biochemistry of addiction has yet to be translated into improvements in treatment…
There is the usual hand-wringing about the low levels of recovery from addiction reported in recent national statistics and then the writer moves on to eulogise a “new approach that acknowledges the underlying biochemistry” that was discussed at the recent FFTB conference.
Its tools are not drugs but dietary changes. The theory is that providing food rich in the precursors of lost neurotransmitters will boost the levels of those chemicals, and thus reduce craving. At the moment, only preliminary trials have been carried out. But they look promising and if larger trials confirm them, a useful, new front in the war on addiction might open up.
How extraordinary. That sounds uncannily like the basis for the latest book and book tour by Visiting Professor Patrick Holford, Dr James Braly and David Miller; where the authors discuss sugar and heroin addiction as equivalent and promise to guide you on quitting both. Patrick Holford is the man of countless specialities (e.g., diabetes, autism, schizophrenia, infertility, allergy, depression) who has recently re-branded himself as an addiction expert. The authors provide recipes of supplements that are tailored to particular addictions: take a capsule of this, an IV of that, and watch your cravings leave your body. How to Quit Without Feeling S**t is long on conjecture and thick with anecdotes about 85% recovery rates from addiction but strangely short on trials and even basic quality evidence such as case-studies that have been submitted to peer-review and reputable journals. There have been several articles about Holford’s all new dietary approach to treating addiction in newspapers and news sources that should have known better: see, e.g., Medical News Today Rescinds a Patrick Holford Press Release; Eat your medicine.
However, this was a conference, Treatment on a plate has passed editorial scrutiny and appeared in The Economist, so there must be something more to it than Holfordism as usual and wishful thinking. Surely there is some substantial evidence-base or there are appropriately rigorous studies.
No.
There is the usual mix of downhome folksiness with a soupcon of science as we read about glutamine as a precursor of Gamma-aminobutyric (GABA).[c] GABA is typically reported to have relaxing, anti-anxiety or anti-convulsive effects. And, making the solution sound as homey and accessible as a glass of warm milk at bedtime, we read that:
glutamine levels can be restored, and production of GABA boosted, by the consumption of an amino acid called N-acetylcysteine (NAC) that is found in nuts and seeds.
Anyone who is muttering “show me the evidence” might be pleased to learn that the article gives an indirect reference to a controlled study that “found that giving NAC to cocaine addicts reduced their desire to use the drug sufficiently for it to be recommended as a treatment”. You might form your own opinion of the matter when you consult Is cocaine desire reduced by N-acetylcysteine?[1] and learn that this study involved 15 participants and the duration was for 2 sessions of 3 days of in-hospital treatment separated by 4 days. The participants were cocaine-free at the time of admission (confirmed by urine screen) and were monitored throughout the stays to ensure that they remained cocaine-free.
The craving and interest assessment is extrapolated from a standardised cue-reactivity procedure involving slides. We mention these details only to illustrate that appropriate qualifications might read: “when presented with cocaine cues, the participants reported reduced interest in cocaine, in some dimensions: these participants were paid for their participation and were already cocaine-free and further monitored to ensure that they had no access to cocaine, for the 3 days of the in-hospital study”. We haven’t even mentioned the results with the surprisingly large SDs or the finding: “No significant medication-related effects were noted for craving, although means for craving within the N-acetylcysteine condition were lower than those in the placebo condition”. The authors conclude:
In the presence of cocaine-related cues, N-acetylcysteine reduced the desire to use cocaine, interest in cocaine, and cue viewing time…It was somewhat unexpected that no significant effects were observed for ratings of craving. However, the pattern of means for craving was consistent with that observed for desire to use and interest, which were highly correlated to craving…and suggests that differences in craving may also have been significant had more subjects been included. In sum, the reduced subjective reports of desire to use and interest in cocaine indicate that N-acetylcysteine may be a promising new treatment and that cysteine-glutamate exchange may be a potential pharmacotherapeutic target for treating cocaine dependence.
Sadly, this last may be no more than wishful thinking as the pattern of the results for 15 participants in this cross-over, placebo-controlled study might also suggest that the pattern of means might not indicate reduction of cravings if more participants were included.
The cocaine study is less impressive than the author of Treatment on a plate suggests but surely there must be less fudging with the encouraging results reported for NAC and the gambling study.
A different study found that NAC reduced the desire to gamble in more than 80% of those addicted to this pastime, compared with 28% of those who were given a placebo.
We think that this is the study in question: N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study.[2] Even from the abstract, a casual reader may note that there were 13 people in the part of the study that is reported in these statistics. There were originally 27 participants in an open-label trial for the supplement. 16/27 of these participants met pre-determined responder criteria which involved a reduction of > or = 30% reduction in Yale Brown Obsessive Compulsive Scale Modified for Pathological Gambling. 13 went on to participate in the double-blind part of this study.
Of those assigned to NAC, 83.3% still met responder criteria at the end of the double-blind phase, compared with only 28.6% of those assigned to placebo.
At the risk of being tedious, we’d like to convert that to actual numbers for you. In the group of 6 participants who received the supplement, 5 still met the responder criteria: in the group of 7 people who received the placebo, only 2 still met the responder criteria. This seems like a very small study with some substantial potential confounders. Oddly enough, the lead investigator for the study would agree with us. In discussion about this work, Dr John Grant stated that the small number of participants meant that his findings could not be considered statistically significant. Further, that although this work shows some tantalising potential connections between the glutamate system and gambling behaviour, Grant stresses that it is important that people should not attempt to self-medicate.
What all of these studies have sort of shown us over the years is that gambling may be a fairly heterogeneous disorder in terms of its underlying biology,” he said. “So some people may respond to one type of medication, where other people with a gambling problem may respond to a different type of medication.”
If Grant is able to prove that an amino acid is effective at treating gambling addictions, he says it would give patients a cheaper — possibly safer — alternative to pharmaceutical drugs. But until his findings are verified, he discourages people from experimenting with health food supplements for gambling addictions. Grant says there’s not much oversight of supplements compared to pharmaceutical drugs. And he says its not clear whether it’s safe to take NAC while pregnant or while taking other medications. [Emphasis added.]
All of which is the sort of nuanced interpretation of research that one expects from a scientist. Presumably, The Economist preferred the unnuanced version and considered such caution to be superfluous (meanwhile, a tiny part of my heart breaks off).
The discussion about serotonin and the putative role for tryptophan in manipulating symptoms of depression is appropriately more tentative but there is insufficient evidence to support even these comparatively bland assertions.
Serotonin is another neurotransmitter that is usually deficient in an addicted brain. This probably accounts for the depressive side of withdrawal symptoms (serotonin receptors in the brain are the target of antidepressant drugs such as Prozac). Serotonin is made from an amino acid called tryptophan, which is found in foods such as meat, brown rice, nuts, fish and milk. Philip Cowen, a psychiatrist at Oxford University, has found that reducing the amount of tryptophan in someone’s diet increases depressive symptoms and also that increasing it can induce a more optimistic outlook.
I rely upon no lesser a source of authority than Philip Cowen in a recent discussion of the related controversies and uncertainties: Serotonin and depression: pathophysiological mechanism or marketing myth?[3]
The notion that impaired serotonin (5-HT) function can lead to clinical depression has a long history but is still controversial…[T]here is now substantial evidence that unmedicated depressed patients have abnormalities in brain 5-HT function; however, the relation of these abnormalities to the clinical syndrome is unclear.
The reader is introduced to familiar bromides about DHA and Omega 3 but the writer admits “the waters are muddy”. It seemed as if some degree of self-awareness might be intruding into the consciousness of either the author or the editor of this piece but this flash of optimism was cruelly dashed when the article continued:
Correlation is not causation, and no decent trials have yet been done to show whether DHA supplements do in fact reduce addiction. Indeed, the whole area is, as it were, under-trialled. As David Smith…pointed out, drug companies are not interested in carrying out such trials because the results, even if favourable, are unlikely to be patentable.
Seriously? Pharma companies are not the only sources of research funding. Oddly enough, any funder likes to see a good corpus of basic science, bench studies, plausible animal models and rigorous hypotheses before funding Phase II and Phase III trials. IRBs also like to see good collections of evidence before they approve a trial as ethical.
GSK recently expressed a dilemma concerning the future of SRT501.
GlaxoSmithKline could put SRT501, its resveratrol formulation, on the market right away, selling it as a natural compound and nutritional pharmaceutical that does not require approval by the F.D.A. “We haven’t made any decisions, but that clearly is an option,” Dr. Vallance said.
If GlaxoSmithKline decides instead to seek F.D.A. approval, it will need to prove that resveratrol is safe in the large doses required for efficacy.
It can be financially advantageous for pharmaceutical companies to market products as supplements because they don’t need to meet the same stringent testing criteria demanded of drugs. Crudely, it would be possible to sell a form of SRT501 without trials and to imply that consumers would need to supplement their diet with substantial dosages to have a therapeutic effect. However, if GSK wished to market a product that makes therapeutic claims, they would need to spend time and money in running trials to establish a safety profile.
Professor Smith is head of the Scientific Advisory Board for FFTB: the CEO is Patrick Holford who is also Head of Science and Education at Biocare which is part of Elder Pharmaceuticals.[d] FFTB also incorporates the Brain Bio Centre: a business that uses a battery of non-standard tests to diagnose conditions/imbalances for which there is negligible or dubious evidence and that promotes supplements as the preferred treatment modality for a range of mental health disorders and addictions. Holford is head of the Brain Bio Centre.
Earlier this year, Smith admitted that the FFTB Child Survey 2007 had not been “a proper job” and that the research wasn’t “rigorous”. It still cost money and the goodwill of the research participants however: sometimes, competence, appropriate oversight of a project, good research design and access to decent scholarship can be as significant stumbling blocks as lack of research funding.
Smith resorts to the stock argument that is used whenever people are defensive about the dearth of research evidence to support their assertions and it has long since palled. Choosing an example from cancer interventions, all-trans retinoic acid (ATRA, a form of vitamin A) is used as a differentiation agent alongside other chemotherapy drugs to treat acute promyelocytic leukemia (APML): it is sold by Roche Labs, amongst others. ATRA is currently under investigation as a therapeutic agent for emphysema.[4]
But this is as sophisticated an argument as Professor David Smith can muster and both the writer and The Economist find it to be worthy of reproduction? It’s hard to believe that this is The Economist and not the Daily Mail. None of this research is ready to bear the freight of hope and desperation of families or professionals who want to discover evidence-based treatments for addiction. Shoddy scholarship, credulous coverage of a conference that is sponsored by supplement manufacturers and companies that offer commercial addiction services, the shadow of Patrick Holford and a regrettable conspiracy-theory-by-the-numbers from Professor Smith, who should have known so much better. What were the writer and the editor of this piece thinking? How could The Economist be so careless of its fine traditions and reputation?
The beauty of Israel is slain upon thy high places: how are the mighty fallen!
Tell it not in Gath, publish it not in the streets of Askelon; lest the daughters of the Philistines rejoice, lest the daughters of the uncircumcised triumph.
Ye mountains of Gilboa, let there be no dew, neither let there be rain, upon you, nor fields of offerings: for there the shield of the mighty is vilely cast away, the shield of Saul, as though he had not been anointed with oil.
Trans: Sedulia Scott David’s Lament for Saul and Jonathan
Notes
[a] Like the New York Times, The Economist has a reputation for extremely high standards; it is said to invest substanital resources in both time and money to fact-check, edit, and re-edit its content.
[b] Patrick Holford in the press release rescinded by Medical News Today after a misunderstanding about the source of the press release:
[A]ddictive substances hijack the brain creating persisting symptoms such as craving, anxiety, insomnia, depression and fatigue. If you scramble your brains with drugs and alcohol, counselling and support, however useful, will not unscramble your brains. However, the brain can be programmed away from addiction by giving a diet high in essential fats and vitamins, and low in sugar, together with specific amino acids that help make the brain’s own ‘feel good’ neurotransmitters.
[c] If you have smelled rancid butter, sweaty socks or cheese puffs, then you are familiar with the odour of GABA and may have some inkling about the taste.
One of the difficulties with Treatment on a plate is the emphasis on the brain and neurotransmitters. Although even oral doses of GABA will affect plasma levels, it doesn’t readily cross the blood-brain barrier (BBB): this is typically attributed to the large size of the molecule and its molecular weight (the BBB tends to be resistant to substances with a molecular weight higher than 500 daltons).
Although GABA, Serotonin and Dopamine will affect plasma levels, they do not readily cross the BBB but remain in the periphery; hence the emphasis on indirect approaches such as supplementing with NAC and tryptophan. However, for GABA, the addition of a phenyl group enables it to move across the BBB: this occurs as Phenibut (beta-phenyl-gamma-aminobutyric acid). But, it is possible that
NAC currently has a better corpus of evidence that Phenibut for use in addiction studies.
[d] The NHS provides pharmaceutical-grade fish-oil capsules to specific groups of patients who have experienced cardiac incidents: until the research behind it was discredited, Evening Primrose Oil used to be available on prescription in the UK.
References
[1] LaRowe SD, Myrick H, Hedden S, Mardikian P, Saladin M, McRae A, Brady K, Kalivas PW, Malcolm R. Is cocaine desire reduced by N-acetylcysteine? Am J Psychiatry. 2007 Jul;164(7):1115-7.
[2] Grant JE, Kim SW, Odlaug BL. N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilot study. Biol Psychiatry. 2007 Sep 15;62(6):652-7.
[3] Cowen PJ. Serotonin and depression: pathophysiological mechanism or marketing myth? Trends Pharmacol Sci. 2008 Sep;29(9):433-6.
[4] Mao J, Goldin J, Dermand J, Ibrahim G, Brown M, Emerick A, McNitt-Gray M, Gjertson D, Estrada F, Tashkin D, Roth M. A pilot study of all-trans-retinoic acid for the treatment of human emphysema. Am J Respir Crit Care Med 2002; 165 (5): 718–23.
Further Reading
Food for the Brain Child Survey 2007: The Promotion
Holford Watch looks at the literature review:
Food for the Brain Child Survey 2007: Review Part 1
Food for the Brain Child Survey 2007: Review Part 2
Food for the Brain Child Survey 2007: Review Part 3
Food for the Brain Child Survey 2007: Review Part 4
Food for the Brain Child Survey 2007: Review Part 5
Holford Watch appeals for help to Professor Holford and two members of the Scientific Advisory Board who approved this report and then looks at the data and analyses:
Food for the Brain Child Survey 2007: Review Part 7
Food for the Brain Child Survey 2007: Review Part 8
Why Don’t Food for the Brain Report Their Survey Results on Supplement Pills Survey: Review Part 9
Food for the Brain Child Survey 2007: Review Part 10
25 Comments
November 5, 2008 at 1:41 pm
An excellent post about the decline of The Economist. Just a couple of geeky points of neuroscience you might like :
1. N-acetyl-cysteine (NAC) is not really a “nutrient” at all although the Economist have painted it as one. NAC is metabolised to cysteine which is an amino acid necessary for lots of things including the production of glutathione which is a cellular anti-oxidant. In this respect NAC is a classic nutrient, but high doses of NAC also have a quite seperate pharmacological effect in the brain which indirectly increases extracellular glutamate. In this regard, it’s just as much a drug as cocaine or morphine. Although obviously, not as much fun.
In fact it’s interesting that Dr Grant, author of the gambling study, chose to title his paper “N-acetyl cysteine, a glutamate-modulating agent…” , in other words treating NAC as a drug. The fact that NAC also happens to be a nutrient, is neither here nor there. In my opinion.
It’s also worth noting that drugs which increase glutamate levels are generally regarded as hazardous because they can cause seizures and, in high doses, kill brain cells. I don’t know if NAC has ever been linked to those problems but this is not something that I would mess around with myself. “Nutrients” are not always safe.
2. I write about tryptophan depletion here. it’s a fascinating experimental technique but the Economist have completely misinterpreted it. Tryptophan depletion is strong evidence that serotonin, while related to clinical depression, is not a “happy hormone” in any simplistic sense!
Admin edit to fix html
November 5, 2008 at 2:54 pm
Thank you, Neuroskeptic. It is always difficult to know where to stop when examining egregious pieces like this when it seems like there is a sticking point in every other sentence.
It does seem as if the current research is so preliminary that it would be unwise to write it up in terms that might encourage readers to self-medicate and to recommend supplement programmes to people in hopes of ameliorating various addictions.
I’m grateful for the further information.
November 5, 2008 at 4:17 pm
A pity that the Economist has closed comments on this as, with a few exceptions, they seem to be dominated by supporters of the Holford view. I was going to post a link. Have you forwarded this to the Sci/Tech editor?
November 5, 2008 at 4:25 pm
This: “Grant says there’s not much oversight of supplements compared to pharmaceutical drugs” made me think of the recent fish oil analyses which I see you have miniblogged.
Apparently, “the test methods and results were disputed by Boots and Tesco, whose products were failed by the website” – but that’s surely a consequence of not having standardisation and regulation in the supplements industry?
The Cowen article on serotonin pills looks fascinating. The story of the serotonin hypothesis is one of the most interesting things I’ve ever stumbled across – and, funnily enough, the last thing I read on it was a blog post by Neuroskeptic.
[Sorry - it's usually the side-issues that I pick up on rather than the meat of a post. No idea why.]
November 5, 2008 at 4:29 pm
It’s always disappointing when these illusions get shattered :(
Interesting that there’s no byline on the article (at least so far as I can see). I’d hate to think that a staff Economist writer was responsible for it…
November 5, 2008 at 5:11 pm
@jonhw – isn’t not having bylines on articles an Economist practice? So it’s very possible it was written by a staff writer.
November 5, 2008 at 5:45 pm
Claire wrote: “it’s very possible it was written by a staff writer”.
We many never know. The Economist is (uncharacteristically) generous about using free-lancers who, by the nature of their occupation, tend to like attribution but The Economist takes the author’s identity into the magazine as a whole and doesn’t give bylines. It is famous (and revered by some starry-eyed individuals *cough*) for its factual probity, its analysis and the impeccable way in which they place an item in context, whether it is society, politics, culture, economics or science. Hang it all, it is cosmopolitan, exudes gravitas, erudition and savoir-faire and I still can’t believe that it printed this. It has veered so far from itself that I’m still waiting to discover that this is a spoof of some sort.
November 5, 2008 at 5:47 pm
Yeah, the Economist always do that. So we don’t know who wrote it but I’d be very surprised if it were any kind of science writer.
November 5, 2008 at 5:50 pm
I’m really glad you picked up on this – I spotted this article when it came out and sighed at the thought that yet another publication was stained by ‘badscience’. This is much more damaging than the usual tabloid article for being in the science part of The Economist, with no mention of ‘the professor’, and nice sciency sounding bits too…
November 5, 2008 at 6:00 pm
Ah, yes. Which I guess is OK when it does exude authority, but in this case…
November 5, 2008 at 6:33 pm
jdc, this is a story with so many separate threads that it is hardly surprising that people pick up on different parts of it.
It’s hard to believe that there are notes that weren’t included but we didn’t mention that the Shelton et al trial that evaluated St John’s Wort was funded by Pfizer who produce both Zoloft and a St. John’s Wort product.
We couldn’t agree more with Grant that one of the most disturbing aspects is the lack of standardisation of dosage and minimum levels of purity for certifiying supplements.
The fish oil analyses were entertaining in some ways as well as disappointing. Fails included: Healthspan (home of Drs Ann Walker, Sarah Brewer, Adam Carey and Thomas Stuttaford); Seven Seas and therefore Professor Caterson whose work was praised lavishly by Patrick Holford and Jerome Burne who failed to notice that a paper on which they rely has been retracted.
One of the oddest things about this article is the sense that Holfordism pervades it but is never explicitly named. Readers would have to know about FFTB, its CEO, the members of the Science Advisory Board, the sponsors of the conference etc. to have any sense of context for this piece but it is lacking. Somehow, all we get is the emphasis on the number of researchers from Oxford. Plus, I may be wrong, but the final paragraph includes Professor Stein as if he were one of the presenters at the conference but we don’t think that he was.
There is some arguing from authority and well as other lapses in critical thinking. Whatever it is, there is just something not quite right about this article.
Shelton RC, Keller MB, Gelenberg A, Dunner DL et al. Effectiveness of St John’s Wort in Major Depression: A Randomized Controlled Trial. JAMA 2001; 285: 19781986.
November 5, 2008 at 7:41 pm
Science Based Medicine has a very good post about pharmaceutical companies isolating active principles from ‘natural products’.
This might be a bit obvious, but for all the talk about “dietary changes…providing food rich in the precursors of lost neurotransmitters “, there seems to be nothing but studies that involve supplements rather than chowing down on nuts, seeds, brown rice etc.
November 6, 2008 at 6:45 pm
@Wulfstan, yes. I suppose that handing out supplements (at least ones of guaranteed purity) is more readily controllable for research purposes than relying on people eating so many grammes of rice, almonds etc.
However, it would be useful to know how much one might need to eat in the way of seeds etc. to achieve a therapeutic dosage of particular substances – and, if eating that would have other consequences.
November 7, 2008 at 12:39 am
The Economist article is now ‘closed to comments’.
’tis a pity
The Economist Critically Evaluates Fanciful Dietary Musings as Viable Treatment Modalities Extrapolated From Hardened Drug Users And Applied To Miserable People (ker-ching!!!) and Those With Addiction To Anything You Like That Will Generate Dosh (ker-ching!!!) For IONistas…..(ker-ching!!!)
Why expect more?
November 7, 2008 at 12:45 am
good stuff – I was surprised to see this guff also reported in addiction today
November 7, 2008 at 7:20 am
nice one steve
November 7, 2008 at 3:39 pm
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