Reply to ‘MDMA can increase cortical levels by 800% in dance clubbers’ Parrott et al.

To the Editor We are grateful to Parrott and colleagues for their letter and the interest shown in our work, which was a secondary analysis of data collected in 2001 as described in our 2006 paper (Wolff et al., 2006), following the development of TaqMan methodology for catechol-O-methyltransferase (COMT) analysis. Although Wolff et al. (2012) was our first full publication describing the increase in cortisol in our sample, in fact this was prefaced by two conference presentations (Tsapakis et al., 2003; Tsapakis et al., 2006). Our 2012 paper reported on a particular phenotype (change in plasma cortisol) in a preand post-clubbing study specifically investigating associations between cytochrome P450 2D6 (CYP2D6) enzyme and COMT enzyme rs4680 genotypes with 3, 4-methylenedioxymethamphetamine (MDMA)-associated change in cortisol. Our aims and hypotheses were quite different from Parrott et al. (2008): moreover, a contrasting methodology for the measurement of cortisol was employed. Specifically, we measured total plasma cortisol whereas Parrott et al. (2008) measured salivary cortisol. Of note, the normal reference range for salivary cortisol concentration is significantly lower than that for plasma cortisol, and the difference between peak and nadir salivary concentrations is more pronounced (Ansari et al., 1982; Laudat et al., 1988; Lo et al., 1992). In addition, Carroll et al. (2008) have noted that late-night salivary cortisol measurement may be problematic owing to various factors including method-dependent cross-reaction with other steroids. It is well known that the hypothalamic–pituitary–adrenal (HPA) axis operates within a tightly regulated circadian rhythm and that, in people with a normal sleep pattern, plasma cortisol concentrations reach a nadir at around midnight that begins to rise 3–4 hr later, reaching a maximum concentration shortly before rising. Table 1 compares the cortisol data from Wolff et al. (2012) with that of Parrott et al. (2008). It is unclear how sampling in the Parrott study was related to the circadian rhythm of cortisol since concentration was measured against MDMA consumption rather than secretion of the glucocorticoid. Of note, their baseline, late-night, pre-drug sample concentrations in apparently drug-naive subjects were already elevated, suggesting dysregulation of the HPA axis already at that point: this could have been affected by factors including the level of exercise undertaken and the awake status of the subjects. There are a number of inaccuracies in the interpretation of our paper by Parrott et al. (2012). in their letter. Firstly, as Table 1 illustrates, our concentrations of cortisol were not ‘110% higher in MDMA users post-clubbing’ and as our subjects were regular (repeated MDMA use) clubbers, the comparison was not with ‘dance clubbers who had not taken MDMA. ’ The magnitude of elevation in (seemingly relatively) drug naïve subjects (as in Parrott et al., 2008) might well be expected to be larger than that in those who consumed MDMA, in the main on a repeated basis (as in Wolff et al., 2012) owing to, for example, neurotransporter downregulation. Secondly, in their penultimate paragraph, the text apparently quoted from Wolff et al. (2012) has been taken out of context. The context is one of individuals of a particular CYP2D6 genotype. Thirdly, the inference that we ‘did not collect samples from clubbers during peak MDMA activity’ would appear to be inaccurate. The pharmacokinetics of MDMA are complex and nonlinear, resulting in zero-order kinetics at higher doses (De La Torre et al., 2004). It is thought likely that this can lead to sustained and higher plasma concentrations of the drug especially if a clubber consumes more than one dose consecutively. MDMA reaches peak plasma concentrations between 1.5 and 3 hours after ingestion (De La Torre et al., 2000a) and may be slowly metabolised for up to eight hours (De La Torre et al., 2000b) and this variability is likely genetically influenced (Aitchison et al., 2012). Thus, there is potential for high concentrations of MDMA to exist in the body when the experiential effects have disappeared. In addition, the contribution of pharmacologically-active metabolites of MDMA (3,4-methylenedioxy-amphetamine (MDA), 3,4-dihydroxymethamphetamine (HHMA) and 3,4-dihydroxyamphetamine (HHA)) to the neuroendocrine effects of the drug remain unclear, with some (such as MDA) likely affecting the secretion of cortisol (Forsling et al., 1999). In summary, although Parrott et al. (2008) reported larger increases in cortisol concentrations than Wolff et al. (2012), consistent with different sampling methodology and non-repeated use of MDMA, clearly there is consistency in the main conclusion from both groups indicating the effect of MDMA increasing cortisol secretion. This is a clinically important and concerning finding. The methodological differences between the two studies emphasize the need for further research in this area, with careful Reply to ‘MDMA can increase cortical levels by 800% in dance clubbers’ Parrott et al.