Depressive mood ratings are reduced by MDMA in female polydrug ecstasy users homozygous for the l-allele of the serotonin transporter

The placebo-controlled pooled study (n=63) investigates the role of 5-HTTLPR polymorphism, a part of the gene that codes for the serotonin transporter in the effects of MDMA (75 mg and placebo). The study found that those who are homozygous (two identical copies, the ‘l-group’) experienced more anxiety, and females within this group experienced a lowering of their depression scores. The study thus concludes there are gender and genotype differences in the effects of MDMA.

Abstract

“MDMA exerts its main effects via the serotonergic system and the serotonin transporter. The gene coding for this transporter determines the expression rate of the transporter. Previously it was shown that healthy individuals with the short allelic variant (‘s-group’) of the 5-HTTLPR-polymorphism displayed more anxiety and negative mood, and had a lower transcriptional efficiency compared to individuals who are homozygous for the l-allele (‘l-group’). The present study aimed to investigate the role of the 5-HTTLPR polymorphism in MDMA-induced mood effects. Four placebo-controlled, within-subject studies were pooled, including in total 63 polydrug ecstasy users (N_s-group = 48; N_l-group = 15) receiving MDMA 75 mg and placebo on two test days, separated by minimally 7 days. Mood was assessed by means of the Profile of Mood States. Findings showed that MDMA induced –independent of sex- a positive mood state, and as a side effect also increased two negative affect states, anxiety and confusion. Anxiety ratings were higher in the l-group and independent of treatment or sex. Depression ratings were lowered by MDMA in the female l-group. Findings indicate that the MDMA-induced reduction in self-rated depressive feelings is sex- and genotype-dependent, with females homozygous for the l-allele showing this beneficial effect.“

Authors: Kim P. C. Kuypers, R. de la Torre, M. Farre, L. Xicota, E. B. de Sousa Fernandes Perna, E. L. Theunissen & Johannes G. Ramaekers

Summary

MDMA is a chemically messy drug that works on a whole range of neurotransmitters. It has pronounced effects on the central nervous serotonin (5-HT) system and causes the serotonin transporter to work in reverse, thereby increasing synaptic 5-HT.

The serotonin transporter gene has a polymorphism that influences its transcriptional activity. The long subgroup has a higher density of 5-HTT and a double of 5-HT uptake capacity compared to the short subgroup.

MDMA has been shown to be effective in the treatment of post-traumatic stress disorder. However, carriers of the s-allele show heightened fear and anxiety, which could feed into potential tailored MDMA-assisted therapy.

This study investigated whether ecstasy users carrying the slow working variants of the SERT genotype experienced less pronounced mood effects immediately after use compared to those who were homozygous for the l-allele.

MDMA made participants feel more vigorous, friendly, elated, aroused, and experienced more positive mood. Sex, genotype, and their interaction with Treatment had no effect on positive mood.

There were main effects of Treatment, Sex, Genotype and their interactions on negative affect scales, with higher anxiety and confusion ratings in the L-group compared with the S-group. There were no main effects of Treatment, Sex, Genotype or their interactions on Anger and Fatigue.

Results

Pearson’s correlation analysis showed that only anxiety ratings were positively related with MDMA concentrations in blood.

Discussion

The present study showed that MDMA induced a positive mood state and elevated feelings of anxiety and confusion. One main effect of genotype was revealed, i.e., individuals in the l-group felt more anxious compared to the s-group.

The results of this study seem counterintuitive since most studies have shown that s-carriers have higher levels of anxiety and are more at risk for developing depression compared to homozygous l-individuals. Another study showed that ecstasy users had a slight tendency for a higher frequency of homozygous s-individuals, although the differences were not statistically significant and samples were in the Hardy – Weinberg equilibrium20. However, a depression baseline pattern comparable to our findings has previously been shown in non-drug using participants22.

The literature on the 5-HTTLPR is not that consistent as it seems, and the level of methylation of the transporter may also be a source of diverging outcomes. MDMA can be seen as a biological stressor, causing a substantial increase in cortisol concentrations17 and therefore potentially affecting methylation. The present study demonstrated that female l-group individuals were more sensitive to MDMA effects, and therefore the results should not be over-interpreted.

In the present study, individuals with a lower SERT activity did not exhibit a disproportionate subjective reaction to MDMA-induced positive mood effects. However, anxiety levels were positively related to MDMA blood concentrations, and the other mood states were unrelated to MDMA blood concentrations.

In the present study, a bi-allelic determination of the 5-HTTLPR was done, but a tri-allelic determination is also possible and might provide more information. The effects of misclassification are minimal, though it is advisable that future MDMA studies include the tri-allelic determination in larger samples.

Results indicate that females homozygous for the l-allele of the 5-HTTLPR showed a beneficial effect of MDMA on self-rated depressive feelings, although this effect was small. MDMA effects on other positive and negative mood states seem to be independent of sex, 5-HTTLPR genotype and MDMA blood concentrations.

Inclusion criteria were age between 18 – 40 years, absence of medication, psychiatric history, major medical, endocrine or neurological conditions, good medical health, minimally three experiences with ecstasy/MDMA, normal weight, body mass index between 18 and 28 kg/m2, and written informed consent.

Methods

A pooled sample of 72 polydrug ecstasy users was included in the study. They were all mentally and physically sound and used cannabis, amphetamine, cocaine, magic mushrooms, LSD and other drugs.

After inclusion, participants were familiarized with the study procedure and questionnaire on a training day, and were asked not to use caffeinated or alcoholic beverages 24 hours before testing. Participants had to pass a breathalyzer ethanol test and a pregnancy test before starting the study.

A permit was obtained from the Dutch drug enforcement administration to administer MDMA (75 mg) capsules.

The Profile of Mood States is a self-assessment mood questionnaire with 72 five point-Likert scale items, representing eight mood states.

Genotyping was done on peripheral blood leukocytes of participants using the Flexi Gene DNA kit (Qiagen Iberia, S.L., Spain). Subjects were split according to genotype and associated 5-HTTLPR functionality.

POMS data were entered into a general linear model (GLM) repeated measures procedure (SPSS, version 24.0), and MDMA concentration data entered into a univariate analysis of variance (ANOVA) with Sex and Genotype as between subject factors. Pearson’s correlations were calculated between POMS scales and MDMA concentrations.