The rather stimulating discussion that arose following Isis the Scientist's critique of a recent study prompted additional blog posts from YHN, Coturnix and drdrA (so far). At the root of much of the bloviating is a comment the original article's authors posted at Isis' blog which appeared to recommend that the most appropriate venue for critical discussion of a scientific paper is the Letters-to-Editors section of the journal in question. Reading additional commentary from the original authors on various of the blogs I am not convinced they meant this point to be as absolute as it came across but it does get me thinking about such discussions.
And I thought I would overview one such prior discussion that bears on some of my posts on MDMA.
Vollenweider and colleagues published a paper in 1998 on the "Psychological and cardiovascular effects and short-term sequelae of MDMA ("ecstasy") in MDMA-naive healthy volunteers."
Vollenweider FX, Gamma A, Liechti M, Huber T.Neuropsychopharmacology. 1998 Oct;19(4):241-51 [publisher link; I think this and the following letters are freely available, if not check the MAPS database linked in the sidebar]. In this study they administered a 1.7 mg/kg oral dose of MDMA to human volunteers.
A letter to the editors of the journal was submitted by Gijsman and colleagues in which they objected to the study:
...we think this study should not have been performed because of the risk ... the authors state that "animal research strongly suggests that a single recreational dose of MDMA is unlikely to produce long-term serotonergic deficits in humans". We disagree with this assertion for the following reason: Repeated administration of MDMA to animals leads to damage of serotonergic axons and terminals which regenerate only to a certain extent and in a very abnormal manner (Fischer et al. 1995). This damage is associated with decreased concentrations of serotonin in the brain. Single dose MDMA also causes a rapid, biphasic decrease in concentration of serotonin in the brains of animals: concentration drops within 1-3 hours restores within 24 hours and drops again after 24-36 hours, lasting for months or even a year (Steele et al. 1994). Therefore it cannot be excluded and even seems likely that administration of a single dose of MDMA to humans causes damage of serotonergic neurons. Even more because primates seem to be more sensitive to both acute and chronic effects of MDMA: in rats, 10 mg/kg (Colado et al. 1995) and in monkeys, 5 mg/kg causes these effects (Ricaurte et al. 1988), a dose that closely approaches the usual recreational dose.If MDMA were a newly developed drug it would almost certainly not be allowed in clinical phase I studies on these grounds.
Readers will recall that I have an interest in these very issues in large part because of ongoing clinical trials (which must certainly surprise the letter authors!)
This letter resulted in a defense from the original study's authors which is extensive, citation heavy and freely available so I won't quote it extensively. Suffice it to say they argued that there was little evidence from either human or animal studies that a single 1.7 mg/kg dose of MDMA was likely to lead to lasting damage. There was one pertinent hook to the continuing story:
In this respect, Ricaurte and colleagues' study (cited by the authors), where a single dose of 5 mg/kg MDMA was given orally to monkeys (Ricaurte et al. 1988), is probably the closest approach to the dose regimen used in our human study. This study found a reduction in 5-HT and 5-HIAA content of about 20% in the thalamus and hypothalamus 2 weeks postdrug.However, as shown above, this does not permit any conclusions as to a possible loss of 5-HT terminals.
Presumably since the Gijsman et al letter suggested there were potential ethical issues at hand with respect to the treatment of human subjects, the editors also addressed the issue. Lieberman and Aghajanian conclude:
Thus, it would appear that while Gjisman et al. (1999) raise valid concerns about this type of research in general and this study in particular, the data do not support the view that single oral doses at 1.7 mg/kg of MDMA (which was one third of the doses used in monkeys by Ricaurte et al. (1988)) are likely to produce damage to serotonin terminals.
These comments would count as trolling a colleague in the blogosphere and sure enough, McCann and Ricaurte soon contributed a viewpoint. Their argument relied on some reasonably accepted* intra-species dose scaling principles.
Unfortunately, when extrapolating the animal data to humans, Dr. Vollenweider et al. (1999) and the Neuropsychopharmacology editorial omitted a critical and fundamental factor in their calculations: the principle of interspecies drug dose scaling (see Mordenti and Chappell 1989). This principle, which is based upon the underlying anatomical, physiological, and biological similarities among mammals, permits researchers to extrapolate animal data to human beings under a variety of experimental conditions. Put simply, smaller animals require higher dosages of drug, on a mg/kg basis, to achieve the same effect. Stated mathematically: Dhuman = Danimal(Whuman / Wanimal)0.7 where D = dose of drug in milligrams (mg) and W = weight in kilograms (Kg). If the known single oral neurotoxic dose of MDMA in a monkey (5.0 mg/kg in a 1 kg monkey) is substituted into the equation, the equivalent dose in a human being weighing 70 kg is 1.4 mg/kg, slightly lower than the 1.7 mg/kg dose used by Vollenweider and colleagues. When identical calculations are carried out using rodent neurotoxicity data (O'Shea et al. 1998), the equivalent MDMA dose in humans is approximately 1.7 mg/kg
Readers will recall that I've tended to ignore this species-scaling argument when discussing the MDMA doses used in the human clinical trials. Instead, I limited my discussion to the size of the typical subject range and the supplemental dosing practices. It is worth recognizing here that most comparisons of dose / exposure to a drug are estimates. Differences in human body size means that human clinical prescriptions (including OTC recommendations) for a fixed mg dose of drug only get in the ballpark. Differences in individual metabolic and other within-species factors mean that using a mg dose per kg bodyweight approach is still only an approximation. Differences in the way two species metabolize different classes of compounds may mean that a dose-scaling equation such as described above holds true for certain types of drugs but not others!
Ultimately, additional data are required to resolve a tight threshold question such as "Is 1.7 mg/kg MDMA likely to cause lasting damage?".
One more response letter from the senior author on the study in question, Vollenweider:
Allometric interspecies scaling is based on the fact that the regression of the logarithm of a pharmacokinetic parameter and the logarithm of species weight is generally linear. As a result, pharmacokinetic (and therefore pharmacodynamic, including toxicity) parameters for a given drug can be estimated in any species if this linear relationship is determined (Ings 1990). Yates and Kugler (1986) and others have criticized the potential inaccuracy of interspecies scaling, noting the 10-fold range of estimates that may be derived depending on which pharmacokinetic and corrective factors are thought relevant. Accordingly, the accuracy of the technique is dependent on the availability of sufficient data.
Vollenweider then throws up some additional smoke screen regarding mechanism of toxicity and potential toxic metabolites but I think the point was made with the general observation. We simply did not then, and still do not now, have very tight estimates about the likely threshold for MDMA-induced damage of a lasting nature. I think the fact that MDMA itself is capable of producing essentially permanent alterations in brain serotonin function is not debatable but the question of threshold is certainly not well resolved.
Getting back to the meta-point of this post, I return to the question of the venue for discussion. Very occasionally a really good discussion of a scientific paper or finding breaks out via exchange of Letters-to-the-Editor in a scientific journal. In my experience, however, this is quite a rare event. The one I detail here was very useful although admittedly many people in the field were already discussing these dose-scaling issues. Still, it brings the discussion out into the open where any first-year graduate student getting up to speed on the field would run across it. A GoodThing.
This is the sort of discussion of a paper that I believe the journals which put effort into such things (such as Nature and PLoS) desire. Their online discussion formats seem to beg for more discussion and wax disappointed with the current state of affairs. The anonymous-comment blog format, however, seems to have no difficulty supporting interesting and fruitful discussion of scientific papers.
*as always I'm not really a pharmacologist and would welcome any necessary correction from experts such as Abel.
Mordenti J, Chappell W (1989): The use of interspecies scaling in toxicokinetics In Yacobi A, Kelly J, Batra V (eds), Toxicokinetics and New Drug Development. New York, Pergamon Press, pp 42-96