Is the recreational use of MDMA related to the prevalence of toxic cardiac valvulopathy? A cross sectional study between non-, incidental and heavy MDMA users.

Several newly developed drugs for the treatment of depression, Parkinson*s
disease and obesity have been removed from the market as they appeared to have
detrimental effects on cardiac valves, leading to restricted valvular motion
that results in regurgitation.1-3 Researchers identified the serotonin 2B
(5HT2b) receptor as a mediator of cardiac valvular fibrosis, comparable to
carcinoid heart disease and development of primary pulmonary hypertension.4,5
The party drug 3,4 methylenedioxymethamphetamine (MDMA or *ecstasy*)
selectively binds to this receptor and produces proliferative actions on human
cardiac valvular cells in vitro, comparable to the aforementioned drugs.6 MDMA
is a popular drug despite being an illicit substance in most countries.
According to the annual report of the national institute of mental health and
addiction, approximately 7.7% of Dutch inhabitants have used MDMA in their
life, which makes it the second most popular recreational drug after cannabis.
MDMA is particularly popular between the age of 20 and 40 years old. In this
age group, up to 22.9% of people have used MDMA at least once and up to 13.1%
report past-year use. MDMA is mostly used on an incidental base, less than once
a month. A small group of approximately 5.2%, reports regular use of several
times a month.7 MDMA is linked to cardiac valvular damage in relatively heavy
users in a case-controlled study by Droogmans et al in 2007.8
Cardiac valve pathology such as mitral or tricuspid valve regurgitation is a
common phenomenon and affects hundreds of thousands of people in Europe. Its
incidence is strongly related to age but is a relatively rare condition in the
age group below 40 years old.9

MDMA is a commonly used drug in the Netherlands, slightly increasing over the
past few years. It has a relatively low addictive effect and the potential
dangers of its use are most probably underreported.7 Possible damage to cardiac
valves has been reported in the past.8 Droogmans et al studied a relatively
small group (N=29) of very frequent MDMA users and compared them with
non-MDMA-users. They found that the use of MDMA was associated with a
significantly higher prevalence of regurgitation of mitral, tricuspid and
aortic valves. Since incidental use (less than once a month) is more common, it
would be of interest to determine if incidental use holds the same potential
risk of cardiac valvular damage compared to heavy use (more than once a month).

The goal of this study is to determine if MDMA use is associated with a
relevant risk of toxic valvulopathy. The popularity of the drug is attributed
to its assumed low-risk profile, but these assumptions could be incorrect due
to underreporting of adverse events related to the drug and unknown potential
side effects such as cardiac valvular damage. Results will be used to gain
insight in potentially harmful side effects of MDMA both infrequent and more
frequent use. With the widespread use of MDMA as a party-drug and recent
interest in its potential benefits on post-traumatic stress disorder, it is
important to clarify its potential long-term hazards. We aim to clarify if the
potential risk of developing cardiac valvular damage is related to heavy use
only or is also increased in persons taking MDMA incidentally.

GENERAL DESIGN
The proposed study is a cross sectional study using three distinct study
groups. These groups are heavy MDMA users (group 1), moderate users (group 2)
and none users (group 3). Group 1 will be matched with group 2 and 3 AND group
2 users will be mathed with group 3. People in the age range 20-55 years old
will be included because this group is known to have the highest MDMA use
(20-35 are mostly current users and >35 years are those who might have had
their peak intake in the 90s dance/gabber scene). There is no age restriction.
The recruiment of participants is laid out in section F1 and will be matched
based on age, sex, education level, country of growing up (due to prevalence of
rheumatic fever).

PRE-SCREENING
If, after recruitment, a possibe participant is interested in participation in
this study a short phone call will be made asking 2 questions:
1. How much MDMA have you taken cumulatively (lifelong dose) by estimation?
2. Do you have a known cardiac disease? In particular a heart valve disease?

In the case of the absence of a cardiac (valve) disease and an MDMA-use that
matched our predifined groups, the participant may proceed to part 1 of the
study.
Patient will be send a patient information form (PIF) to their home adress.
After this a personalized link (via Castor) will be send to answer a more
detailed questionaire.

PART 1 - QUESTIONAIRE
Subjects will be asked to fill out a questionnaire. First they will be asked to
specify their medicla history. Known cardiac valvular pathology (i.e. mitral
valve prolapse, bicuspid aortic valve), past endocarditis, congenital and
ischaemic heart disease could influence results and should therefore be
excluded. Other factors of influence are concomitant prescript drug (ab)use and
non-prescript drug abuse, therefore subjects will be asked to report on their
drug use and abuse. Known prescript drugs that cause toxic valvulopathy are
ergot derivatives (f.e. ergotamine in migraine patients), pergolide,
benflurorex, fenfluramine and dexfenfluramine. The latter four drugs are no
longer available on the market. Long-term use (definied as > 2 weeks) will be
an exclusion.

Second subjects will be asked to make an estimated guess (or estimation) about
their previous MDMA use (in pills). To aid subjects making this estimate they
will be guided to write down their MDMA use per year. Although the analysis is
centered around the cumulative amount of pills, we do want to make an estimated
cumulative dose in gram. To do so, we use the average MDMA-pill strength per
year that is published on the website of Trimbos institute. Finally subjects
will be asked about their use of other illicit substances that might act on the
2B (5HT2b) receptor: 2-CB (2,5-dimethoxy-4-bromophenethylamine), 4-FA
(4-Fluoroamphetamine), 3-MMC or methaphedrone (3-Methylmethcathinone), 4-MMC or
mephedron (4-methyl methcathinone).

After completion of the questionaire both the exclusion criteria and estimated
MDMA-use will be checked to see if patient can proceed to the heart ultrasound.
It is however possible that a participant can still be excluded after
pre-sreening by phone AND filling out the questionaire. For example: MDMA-use
too low, >2 weeks use of ergotamine. This option is explained in both the study
protocol, the patient information form and will be explained to the participant
before filling out the questionaire. We do however expect very few participants
to be excluded after the questionaire due to the pre-screening by phone. The
results of the participants who are excluded after part 1 will be used in our
analysis.

PART 2 - HEART ULTRA SOUND
After a fully filded out questionaire subjects that do not meet any of the
exclusion criteria proceed to a full echocardiogram. Thorough evaluation of the
function of all heart valved will be done, besides general function/dimenions
calculations.

ANALYSIS
Participants in group 1 and 2 will be matched prospectively and individually to
a control, based on age and sex. For age distribution groups will be used:
20-25 years, 25-30 years and on untill 50-55 years. After inclusion of a
participant in group 1 or 2 we prospectively recrute a sex and age matched
control. Participants from group 1 and 2 will be matched to a participant in
group 3 in a 1-to-1-setting. Therefore we estimate to screen between 60 and 120
participants in group 3. Some participants in group 3 could serve as a much
more than once, but this depends on the caracteristics of this control-person.

The primary outcomes are being described in the section: 'Primary study
parameters/outcome of the study'. The primairy and secondary outcomes will be
compared be using a Chi Square Test. Univariabele and mutlivariate logistic
regression analyses will be done to study the use of MDMA on the primary and
secondary outcomes. Also for independent variables (f.e. level of highest
education) univariate logistic regression will be done. Variables with a
signifcant association (P < 0.1) will be included in a stepwise multivariabel
logistic regression model to study the corrected effect of MDMA on the primary
and secondary outcomes.


FINAL
Every subjects will receive a written report via post within 1 week. In the
case of significant heart valve abnormalities (f.e. at least grade 2 out of 4
insufficiency (=leak)) or another unexpected finding the subject will also
receive a phone call by one of the study doctors within 1 week. Their GP and/or
treating medical specialist will also be informed and a follow-up trajectory
will be discussed with the participant.

Last, every subject wiil receive an information letter about the risks of MDMA
use. If, judged by the study doctor, a subject might meet criteria of drug
abuse, drug counselling will be offered.

This study renders no risks for participants. Participation consist of filling
out a questionnaire and a 45-minute echocardiographic examination. The possible
benefit for any participant is a complete evaluation of cardiac dimensions,
function en heart valve (dys-)functioning. In the case of abnormal findings
paticipants will both receive phonecall and we will inform their GP or medical
specialist (or both) to discuus further follow-up as needed.) (see study
protocol and PIF)