Introduction
Since 1986, MDMA has been administered to over 230 people in uncontrolled and
controlled clinical or laboratory settings, with data from previous studies reviewed in the
IB and the 2002 update to the IB. Past research has investigated physiological (for
example Lester et al. 2000; Mas et al. 1999), subjective (for example Cami et al. 2000;
Vollenweider et al. 1998), neuroendocrine (for example Grob et al. 1996; Harris et al.
2002), immunological (for example, Pacifici et al. 2002; Pacifici et al. 2000), and long-
term effects (for example, Vollenweider et al. 2000) of MDMA. In addition, researchers
published one imaging (Gamma et al. 2000A) and one EEG (Frei et al. 2001) study.
MDMA was tolerated in samples familiar and unfamiliar with the effects of Ecstasy, and
no serious adverse events were reported in these studies. Most studies reached similar
conclusions about the effects of MDMA in humans, finding that MDMA shared effects in
common with some psychostimulants and some hallucinogens, and some unique features
supporting the placement of MDMA in a novel drug class, the entactogens (see Nichols
and Oberlender 1990). Previous reviews demonstrated the importance of serotonin
release on producing acute subjective and physiological effects, but also found roles for
dopamine and the serotonin 5HT2A receptor. To date, data published or presented from
clinical trials located in 2003 do not contradict previously reported findings, though some
studies address new areas of research. More detailed coverage of past research can be
found in the IB (Baggott et al. 2001) and the 2002 update to the IB (Jerome and Baggott
2003).
Human trials of MDMA were performed in Spain, the US and the Netherlands. Six
research papers have appeared in the last year (Farre et al. 2004; Lamers et al. 2004;
Pacifici et al. 2004; Pichini et al. 2003; Pizarro et al. 2003; Tancer and Johanson 2003),
and two teams presented data at conferences (Tancer et al. 2003; Ludewig et al. 2003).
Earlier research conducted by five of six teams appeared in the original Investigator's
Brochure, and the research from all six teams was reviewed in the 2002 update of the IB.
In three of six cases, recently published reports draw on the same samples represented in
previously published reports (Lamers et al. 2004; Pichini et al 2003; Pizarro et al. 2003).
In a fourth case, data from a manuscript now published but previously in press was
presented to institutional review boards, though it did not appear in the publicly available
review (Tancer and Johanson 2003). The conference presentation by Ludwig and
colleagues drew on a sample that was similar, but not identical, to a sample described in
previous presentations (e.g. Vollenweider et al. 2001; 2000).
Preliminary data from a study from a study of MDMA-assisted therapy in people with
posttraumatic stress disorder (PTSD) was presented to institutional review boards in the
2002 update of the IB. This study remains inactive, as described below. However,
another study of MDMA-assisted therapy in people with PTSD has commenced.
Four of six published reports investigated physiological effects of MDMA (Farre et al.
2004; Lamers et al. 2004; Pacifici et al. 2004; Tancer and Johanson 2003), and three
reports investigated subjective effects or effects on psychomotor tasks and cognition
(Farre et al. 2004; Lamers et al 2004; Tancer and Johanson 2003). One report
specifically investigated rewarding effects (Tancer and Johanson 2003), and another
report investigated possible causes of immunological effects (Pacifici et al. 2004). Two
reports investigated MDMA pharmacology and deposition in biological fluids (Pizarro et
al. 2003; Pichini et al. 2003). Finally, one report described the effects of an initial dose
of 100 mg MDMA followed by a second 100 mg dose given 24 hours after the initial
dose (Farre et al. 2004).
Conference presentations included preliminary findings from research on MDMA effects
on body temperature (Tancer et al. 2003, Presentation at the 65th Conference of the
College on Problems of Drug Dependence), and preliminary findings from a study of
cognitive performance in MDMA-naïve individuals one month after receiving MDMA
(Ludewig et al. 2003, presented at the 58th Annual conference of the Society for
Biological Psychiatry). All studies described above used randomized, double-blind,
placebo-controlled designs, and all save one study relied on a within-subjects design.
(The study performed by Pacifici and colleagues was incompletely crossed, and did not
have a placebo-no paroxetine condition).
To date, one trial of MDMA-assisted psychotherapy was begun in Spain, and a second
trial of MDMA-assisted therapy has commenced in the US. The MAPS-sponsored trial
of MDMA in women with posttraumatic stress disorder (PTSD) arising from sexual
assault is still inactive due to political pressure from the Madrid Anti-Drug Agency,
despite receiving permission from the Spanish Ministry of Health (Doblin 2003).
Preliminary findings from this study were provided to institutional review boards in the
most recent update to the IB, with no serious adverse events, and no signs of worsening
symptoms, occurring in participants enrolled in this study. Volunteers in the study
underway in the US will undergo two experimental sessions where they will receive 125
mg MDMA or placebo, as well as up to ten non-drug assisted therapy sessions. Twelve
of 20 participants will receive MDMA, and eight will receive placebo. To date, two
subjects have undergone experimental psychotherapy sessions, and though it is not
known whether MDMA or placebo was administered during the sessions, no serious
adverse events have been reported so far (Mithoefer 2004).
Group demographics and characteristics of volunteers taking part in all studies published
or presented in 2003 were similar to those reported in previous research studies. These
included absence of any major physical or mental illnesses, as established through
physical examination and psychiatric interviews, and having no substance abuse
disorders save those for nicotine and MDMA, when relevant. All published reports
restricted enrollment to people reporting past use of Ecstasy, though one conference
presentation examined an MDMA-naïve sample. Four of six studies enrolled male
participants only (Farre et al. 2004; Pacifici et al. 2004; Pichini et al. 2003; Pizarro et al.
2003), whereas two studies (Lamers et al. 2004; Tancer and Johanson 2003) and both
conference presentations (Ludewig et al. 2003; Tancer et al. 2003) enrolled both men and
women. The Spanish team typed all volunteers for CYP2D6 function (enzyme involved
in MDMA metabolism), while the other research teams did not type volunteers for
variance in CYP2D6 function. As noted in the IB and the 2002 update to the IB,
metabolism of MDMA involves several enzymes, and it appears that being an extensive
CYP2D6 metabolizer may be less important than initially believed.
Doses of MDMA employed in all recently published studies ranged from 52.3 mg
(approximately 1 mg/kg for one subject in Tancer and Johanson 2003) to 171.8 mg (2
mg/kg for a subject in Tancer and Johanson 2003). Other doses included 1 mg/kg across
other subjects in Tancer and Johanson 2003, 75 mg (Lamers et al. 2004), 100 mg (Farre
et al. 2003; Pacifici et al. 2004; Pichini et al. 2003; Pizarro et al. 2003), approximately
103 and 119 mg MDMA (1.5 and 1.7 mg/kg MDMA (Ludewig et al. 2003), and other 2
mg/kg doses in Tancer and Johanson 2003. One study administered two successive 100
mg doses, with one dose given a day after the first dose (Farre et al. 2004), so participants
in this study received a cumulative dose of 200 mg over 48 hours. All doses were well-
tolerated by study volunteers and no adverse events were reported during the course of
any of the published reports.
Reports continued to find that MDMA has sympathomimetic effects (Farre et al. 2004;
Tancer and Johanson 2003), and confirmed its immunosuppressant and anti-inflammatory
actions (Pacifici et al. 2004) initially described in the IB. Current research also
confirmed previous reports of the stimulant-like and hallucinogen-like subjective effects
of MDMA, including elevation in both positive and negative mood (Farre et al. 2004;
Pacifici et al. 2004; Tancer and Johanson 2003), and slight perceptual alterations.
MDMA-induced elevation in cortisol and prolactin were also confirmed (Farre et al.
2004; Pacifici et al. 2004; Tancer and Johanson 2003). One study makes direct
comparisons between MDMA, the psychostimulant d-amphetamine and the serotonin
releaser and 5HT2C agonist mCPP (Tancer and Johanson 2003), finding that MDMA
shares features with each of the other compounds. Another study investigated the
relationship between serotonin release and the immunological effects of MDMA via
pretreatment with the serotonin uptake inhibitor paroxetine (Pacifici et al. 2004),
demonstrating a role for serotonin release in the immunological effects of MDMA
(Pacifici et al. 2004). Thus these studies elaborated on or sought to clarify findings noted
in previous reports (e.g. Pacifici et al. 2002; Pacifici et al. 2000).
Novel findings include a profile of MDMA effects on skills and tasks related to driving a
motor vehicle (Lamers et al. 2004), an assessment of the reward value of MDMA (Tancer
and Johanson 2003), the first description of tolerance to some subjective, physiological
and neuroendocrine effects of MDMA after a second dose given 24 hours after the first
dose (Farre et al. 2004), preliminary findings of lack of long-term effects on cognitive
function (Ludewig et al. 2003, Presented at 58th Conference for Biological Psychiatry)
and preliminary findings of slightly elevated body temperature in both a cold and a warm
room (Tancer et al, presentation at 65th Conference of the College on Problems of Drug
Dependence). The profile of MDMA effects related to driving found psychomotor skills
such as visual tracking and reaction time improved after 75 mg MDMA, little changes in
tasks involving executive function such as word fluency, and impairment in tasks
involving time estimation for moving objects (Lamers et al. 2004). A measure of reward
value relying on choices made between the test drug and receiving or giving up money
found that MDMA had high reward value in a sample reporting previous use of Ecstasy
(Tancer and Johanson 2003). However, none of the newly reported findings or
presentations of preliminary findings call into question any of the conclusions reached in
the IB concerning the effects or safety of MDMA.
In conclusion, research presented or reported in 2003 employed similar designs and doses
of MDMA to those used in previous studies, and administering MDMA in controlled
settings continues to produce no adverse events. Volunteer characteristics are similar to
those in previous reports, and in several cases data has been gathered from samples
featured in previous reports. None of the newly reported findings differ significantly or
are in conflict with earlier findings reported either in the IB or in the 2002 update of the
IB.
Physiological Effects
None of the recent publications or presentations described surprising findings concerning
the physiological effects of MDMA in humans. All research teams assessing
cardiovascular changes found elevated blood pressure and heart rate or pulse, and those
assessing changes in body temperature continued to report slight elevations in body
temperature (Farre et al. 2004; Tancer and Johanson 2003). Tancer and Johanson
measured blood pressure, heart rate and body temperature after 1 and 2 mg/kg doses of
MDMA (approximately 70 and 150 mg) in 12 volunteers found that peak changes in
these variables appeared no later than 2 hours after drug administration (Tancer and
Johanson 2003), suggesting that the likelihood of adverse events declines after this point
in time. The recent findings described do not differ significantly from previous research
presented in the IB and the 2002 update to the IB (see for example Grob et al. 1996;
Lester et al 2000; Liechti and Vollenweider 2001; Mas et al. 1999; Tancer and Johanson
2001).
2 mg/kg MDMA elevated systolic and diastolic blood pressure above values seen after
placebo (Tancer and Johanson 2003). Peak elevation in systolic and diastolic BP
appeared 1 hour after drug administration.
2 mg/kg MDMA also elevated heart rate significantly above values reported after
placebo, with the greatest increase in heart rate seen at 20 BPM above normal, an
increase similar to that seen during moderate exercise (Tancer and Johanson 2003). Peak
increase in heart rate was seen 1 h post-drug. This study reported that when compared to
d-amphetamine and mCPP, MDMA produced the greatest increases in blood pressure and
heart rate. However, values for MDMA were still very similar to those seen for the other
compounds studied.
A second dose of 100 mg MDMA given a day after an initial 100 mg dose elevated blood
pressure and heart rate, doing so to a greater degree than seen after the initial dose (Farre
et al. 2004). However, plasma MDMA levels after this dose are similar to values
association with the slightly higher dose of 125 mg. Given the higher plasma MDMA
levels after the second dose, cardiovascular changes are actually somewhat lower than
expected, suggesting tolerance to these effects. A greater number of subjects had peak
SBP above 140 mmHg after the second administration than after the first. In contrast, the
increase in heart rate seen after the second dose of MDMA was only slightly greater than
that seen after the first dose, and the second dose of MDMA, like the first, failed to
significantly increase body temperature.
Only two published reports assessed body temperature after MDMA (Farre et al. 2004;
Tancer and Johanson 2003). Farre and colleagues assessed temperature after an initial
dose of 100 mg MDMA, and a subsequent dose of the same amount given 24 hours after
the first dose, finding no significant increases in body temperature after either dose (Farre
et al. 2004). Tancer and colleagues assessed changes in body temperature after 2 mg/kg
MDMA, finding a slight elevation in body temperature that was comparatively lesser
than that produced by 20 mg d-amphetamine. Peak elevation in body temperature was
seen 2 hours after drug administration. At no time did the increase in body temperature
exceed 1 degree Celsius.
Tancer and colleagues also presented preliminary findings concerning the role ambient
temperature might play in changes in body temperature after 2 mg/kg MDMA at the
2003 CPDD conference (Tancer et al, 2003, Presentation at 58th Conference of the
College on Problems of Drug Dependence). Ambient temperature did not appear to alter
the slight increase in body temperature after 2 mg/kg MDMA, with subjects in a cold
room (18 degrees C or 64 degrees F) exhibiting the same increase as subjects in a warm
(30 degrees C, or 86 F) room. Though data was only collected from a very small sample
of four volunteers, the findings suggest that humans are less sensitive than other species
to the thermoregulatory effects of MDMA. It is also possible that significant changes in
thermoregulation only occur after higher doses. None of the data presented or published
so far contradicts previously reported conclusions in the IB and or data reported at the
2002 update to the IB, with all reports indicating that MDMA is sympathomimetic and
produces a slight increase in body temperature.
Subjective Effects and Side Effects
Only two recent publications explicitly assessed the subjective effects of MDMA (Farre
et al. 2004; Tancer and Johanson 2003), though another report mentions subjective
effects (Pacifici et al. 2004). Tancer and Johanson assessed subjective effects via several
instruments, including the Addiction Research Center Inventory (ARCI), the Profile of
Mood States (POMS), the Hallucinogen Rating Scale (HRS), visual analog scales (VAS),
and an end of session questionnaire. Farre and colleagues used a Spanish version of the
ARCI and the same visual analog scales employed in earlier studies performed by the
same team (Cami et al. 2000; Hernandez-Lopez et al. 2002).
MDMA increased positive and negative mood (Farre et al. 2004; Tancer and Johanson
2003). Tancer and Johanson reported that peak negative mood 1 h post-drug, and peak
positive mood 2 h post-drug. MDMA also increased feelings of energy, and unlike a
previous reports (Cami et al. 2000), it did not increase sedation (ARCI "PCAG") (Farre et
al. 2004; Tancer and Johanson 2003). Volunteers in one study reported increases in
feeling social and stimulated, and decreased feelings of hunger (Tancer and Johanson
2003), and volunteers in the other study noted changes in perception, euphoria and
stimulation (Farre et al. 2004). When compared with 20 mg d-amphetamine and 0.75
mg/kg mCPP, 2 mg/kg MDMA increased talkativeness, positive mood and feeling high
(Tancer and Johanson 2003). MDMA produced increased scores on five of the six scales
of the HRS, including scales measuring changes in affect, perception, cognition and
somatic experience, though it is notable that these changes also appeared after mCPP. A
second dose of MDMA produced slightly more stimulation, slightly less sedation, and
apparently increased perceptual alterations, but again not to the degree expected from
examining plasma MDMA levels, leading Farre and colleagues to suggest that their
results indicate tolerance to specific MDMA effects. Volunteers in both studies had
previous experience with Ecstasy, and so it is possible that some of the subjective effects
reported in this study may arise from their expectations. However, one of the two studies
was a randomized, double-blind comparison of two doses of three different substances,
somewhat reducing the chance that responses were guided by previous knowledge of
Ecstasy effects. As well, changes in subjective effects were similar to those reported in
drug-naïve samples (see Liechti et al. 2001; Vollenweider et al. 1998).
When Tancer and Johanson asked volunteers in this study to guess what drug they had
received during each session, apparently both MDMA and mCPP were identified as
either hallucinogens or MDMA-like drugs (empathogens, an alternative term for
entactogens). In contrast, d-amphetamine was correctly identified more often than it was
mistaken for a hallucinogen or an MDMA-like drug. This somewhat surprising finding
suggests that MDMA may share more features with a serotonin releaser that does not
produce euphoria or stimulation than it shares with a psychostimulant.
When subjective effects were analyzed across time (Tancer and Johanson 2003), peak
effects for elevated positive mood, such as POMS "Elation" and "positive mood" and
ARCI MBG and BG (scales for euphoria and stimulant-like effects), and visual analog
measures for Social, appeared 2 hours post-drug, whereas elevation in negative mood
(such as POMS Anxiety, ARCI LSD (scale for anxiety and unpleasant or unusual somatic
effects) appeared 1 hour post-drug, at a time coinciding with most peak physiological
effects, raising the possibility that the peak in positive mood and related effects occurs at
a different time from the peak in negative mood-related effects.
In their report, Pacifici and colleagues noted that three days of paroxetine pretreatment
attenuated euphoria in people receiving 100 mg MDMA. This report does not describe
how subjective effects are assessed, nor does it give any further detail on subjective
effects of MDMA, but the findings are comparable to effects of a single pretreatment
with the serotonin uptake inhibitor citalopram (Liechti et al. 2000A), and support the
importance of serotonin release in producing the subjective effects associated with
MDMA.
Tancer and Johanson (2003) sought to assess the reward value of MDMA through using
the Multiple Choice Procedure (MCP) in12 MDMA-experienced people. At the end of
each session, volunteers responded to a series of twenty choices between the drug they
had received and receiving or giving up a specific amount of money. The point at which
a volunteer chooses to receive or give up money rather than receive the test drug is
considered an indicator of reward value. The MCP was administered for placebo and
both doses of all three comparison drugs (1 and 2 mg/kg MDMA, 0.5 and 0.75 mg/kg
mCPP, and 10 and 20 mg d-amphetamine). Only 2 mg/kg MDMA and 20 mg
amphetamine attained significantly higher reward value than placebo, with volunteers
assigning the highest reward value to 2 mg/kg MDMA. These findings are comparable to
previous findings that MDMA has some abuse potential (e.g. Cottler et al. 2001; Jansen
1999; Topp et al. 1999; Von Sydow et al. 2002). However, it should also be noted that a
review of trials performed on samples of mostly MDMA-naïve volunteers who received
1.5 to 1.7 mg/kg MDMA (Liechti et al. 2001) failed to find any interest in self-
administering MDMA outside of a laboratory setting.
None of the studies published in 2003 formally assessed occurrence of side effects,
though one paper noted that it was difficult to collect saliva from subjects after MDMA
administration, (Pichini et al. 2003), and another noted that people felt less hungry after
MDMA (Tancer and Johanson 2003). The profile of somatic effects (both unwanted and
"neutral" or non-valenced) is well-established, with detailed information found in the IB.
Researchers have not described any new side effects occurring in volunteers enrolled in
their studies.
Published findings in 2003 did not employ any volunteers with major mental disorders.
However, data from an unpublished and currently halted study of MDMA-assisted
psychotherapy in women with PTSD arising from a sexual assault was presented in the
2002 update to the IB (Bouso 2003, personal communication). The women taking part in
this study were not worse off after the study, and some showed signs of improvement.
Taken together, the findings reported in these studies are consonant with those reported in
the IB (see Cami et al. 2000; Grob et al. 1996; Vollenweider et al. 1998) and the 2002
update of the IB (see Harris et al. 2002; Hernandez-Lopez et al. 2002; Liechti and
Vollenweider 2001; Tancer and Johanson 2001). Previous research has indicated that
MDMA produces stimulant-like and hallucinogen-like effects, with inconclusive but
suggestive findings concerning unique pharmacological effects. Current research
findings are in agreement with those from previous studies. Some of the findings from
Tancer and Johanson could be interpreted as offering support for unique pharmacological
effects including increased sociality and friendliness after MDMA, as hypothesized to
occur in "entactogens" like MDMA.
Subjective effects after a second dose of MDMA were generally greater than those
reported after an initial dose (Farre et al. 2004). However, the increase in strength of
effects is less than expected from plasma MDMA levels, suggesting tolerance to some
effects when a second dose is given 24 hours after an initial dose. This study did not
describe effects appearing after two more closely-spaced doses, though the same team
has conducted immunological studies of two doses of 100 mg given four hours apart
(Pacifici et al. 2001).
Psychomotor and Cognitive Function
Previous controlled and uncontrolled studies have formally or informally examined
MDMA effects on psychomotor and cognitive processes (Cami et al. 2000; Downing
1985; Frei et al. 2001; Gamma et al. 2000A; Vollenweider et al. 1998). As discussed in
the IB, MDMA failed to alter performance on most tasks, such as simple reaction time
tasks or Stroop performance (Cami et al. 2000; Gamma et al. 2000A; Vollenweider et al.
1998), but did alter digit-symbol substitution performance (Cami et al. 2000) and
decision making (Downing 1986).
Spurred on by this research, and by reviews and reports of traffic accidents and difficulty
driving after Ecstasy use, researchers in the Netherlands decided to study the effects of 75
mg MDMA on tasks and skills related to driving a motor vehicle in eight men and four
women previously experienced with Ecstasy (Lamers et al. 2004). Ethanol (0.5 g/kg) and
placebo served as comparison substances. Surprisingly, MDMA failed to alter and
sometimes even improved volunteers' performance on some tasks. Participants given 75
mg MDMA performed a word fluency task (generate words meeting specific criteria
during a given interval) and a computerized Tower of London task at levels similar to
those seen after placebo. MDMA did not affect eye-hand tracking, and it improved
psychomotor speed compared to placebo, with responses were faster after MDMA than
after placebo. However, MDMA did interfere with volunteers' ability to estimate the
time it took for an object to move from one place to another when the object was hidden
from view. It is possible that alteration in time perception, noted in previous studies,
(Vollenweider et al. 1998) might make it more difficult to estimate amount of time
needed for a hidden object to pass from one point to another.
The findings of Lamers and colleagues clarify and elaborate on previous findings
concerning the acute effects of MDMA. Though these new findings may appear to be in
conflict with some earlier reports and reviews of impaired driving or driving-related
abilities after MDMA (i.e. Logan et al. 2001), differential effects on specific tasks has
already been suggested (Cami et al. 2000). Even if MDMA does improve some driving-
related skills, such as psychomotor speed, it still appears that MDMA might impair other
driving-related skills, such as time estimation for moving objects.
It should be noted that the same team of researchers tested driving related skills more
directly through a driving simulator in a quasi-experiment conducted in a sample of 15
men and five women (Brookhuis et al. 2004) one hour after they had self-administered
Ecstasy tablets, and again after having attended a club or party and taken Ecstasy and
other drugs, with the second driving simulation task performed four to five hours after the
first simulated drive. Simulated drives post-drug were compared to presumably drug-free
performances by the same sample. Brookhuis and colleagues found that self-
administration of Ecstasy was associated with impaired driving skills, including a greater
acceptance of narrow gaps between simulated vehicles, and impairments were greater
when Ecstasy was combined with other substances. Incidence of (simulated) crashes
increased after Ecstasy when compared with presumably drug-free performance, and
increased again after returning from a dance event or party. A control group of 13 people
with no history of Ecstasy use showed slightly less risky driving during a presumably
drug-free session, indicating that impaired performance and increased crashing might be
associated with repeated use of Ecstasy, or with pre-existing factors associated with drug
use, such as risk-taking. However, findings of impaired driving acutely after Ecstasy
self-administration, and especially after the coadministration of Ecstasy and other drugs,
are consonant with previous reports of erratic driving after the use of Ecstasy alone or
with other drugs (Logan et al. 2001).
Performance on a simple reaction time (RT) task and the digit-symbol substitution task
(DSST) was assessed in volunteers after an initial dose of 100 mg MDMA, and after a
second dose given 24 hours later (Farre et al. 2004). This study also measured the
changes in extra-ocular muscles that can lead to convergent squint (esophoria) and
divergent squint (exophoria). Results reported were similar to those first reported by
Cami and colleagues, that of unimpaired reaction time, slightly impaired DSST
performance, and significant esophoria, both after the initial dose and after the second
dose of MDMA. The second dose of MDMA did not produce greater esophoria than the
initial dose.
Neuroendocrine Effects
Three studies evaluated stress hormone release after MDMA (Farre et al. 2004; Pacifici et
al. 2004; Tancer and Johanson 2003). In line with previous research, (Grob et al. 1996l;
Harris et al. 2002; Mas et al. 1999; Vollenweider et al. 1998), these studies found that
MDMA elevated levels of the stress hormones cortisol and prolactin.
A study in twelve men found that 100 mg MDMA increased levels of plasma cortisol and
prolactin, with levels of both hormones peaking 4 to 5 hours post-drug (Pacifici et al.
2004). The same study reported that pre-treatment with the serotonin uptake inhibitor
paroxetine reduced cortisol and prolactin levels after MDMA. Another study found that
2 mg/kg MDMA produced significant increases in salivary cortisol when compared with
placebo (Tancer and Johanson 2003). The researchers detected peak hormone levels 3
and 2 hours post drug in a sample of 12 volunteers that contained both men and women
(Tancer and Johanson 2003). Findings from both studies are in agreement with previous
reports of increased cortisol and prolactin after similar doses of MDMA (Grob et al.
1996; Harris et al. 2002; Mas et al. 1999; Vollenweider et al. 1998). Finally, a third study
found increased levels of prolactin and cortisol in nine men after an initial dose of 100
mg MDMA, and again after an additional 100 mg administered a day later (Farre et al.
2004). Cortisol levels after the second dose of MDMA were even greater than cortisol
after the first dose, but prolactin release after the second dose of MDMA was no greater
than prolactin levels seen after the first dose. These somewhat divergent findings suggest
that MDMA-related changes in prolactin are reduced after repeated dosing. Cortisol is
not similarly affected. This data also suggests that the effects of MDMA on these two
hormones differ on at least one aspect or process.
Immunological Effects
To date, Pacifici and colleagues are the only team of researchers studying the
immunological effects of MDMA in humans (Pacifici et al. 2004; Pacifici et al 2002;
Pacifici et al. 2001; Pacifici et al. 2000). They have found generally immunosuppressive
and anti-inflammatory effects that last for about one to two days (Pacifici et al. 2000;
2001). All subjects in these studies have been men reporting some previous experience
with Ecstasy.
Pacifici and colleagues continue to elaborate on their initial findings. In their most recent
publication (Pacifici et al. 2004), they investigated the role played by serotonin release in
the effects of MDMA on the immune system. Volunteers received a daily dose of 20 mg
paroxetine for three days prior to receiving 100 mg MDMA. Paroxetine pretreatment
attenuated many of the immunological effects of MDMA, such as reduced numbers of
CD4 cells, increased numbers of NK cells and reduced production of the pro-
inflammatory cytokine IL-2. Paroxetine pretreatment completely prevented MDMA
from dampening lymphocyte proliferation after encountering a potential antigen, and
strongly inhibited an increase in the anti-inflammatory and immunosuppressive cytokine
IL-10. Overall, findings suggest that at least some of the immunological changes
produced by MDMA, are the direct or indirect result of serotonin release. However,
other neurotransmitter systems, such as norepinephrine and dopamine, may be more
strongly involved in other immunological changes, such as reductions in CD4 cells and
increases in NK cells. Paroxetine pretreatment also halved MDMA-associated increases
in cortisol and prolactin release, suggesting that some of the immunological changes may
be related to changes in neuroendocrine function.
Research findings are in agreement with earlier studies performed by Pacifici and
colleagues. While it offers a possible and partial explanation for the immunological
effects of MDMA, it does not alter our understanding of these effects. A pair of
immunologists who reviewed the effects of drugs acting on serotonin and dopamine (like
cocaine and MDMA) proposed other explanations for the immunological effects of these
drugs as well, noting that some immune cells sport serotonin and dopamine receptors
(Gordon and Barnes 2003). All studies conducted by Pacifici and colleagues have been
restricted to men, but to date, there is no reason to expect different results in women. The
immunological effects of MDMA are transient and are comparable to the effects of
consuming four to five alcoholic drinks. Nevertheless, caution may be appropriate when
administering MDMA to people with suppressed immune systems.
Pharmacology
To date, pharmacological studies of MDMA have either consisted of investigations into
the roles played by specific neurotransmitters in the physiological and subjective effects
of MDMA (see Vollenweider 2001 for a review and summary) or examinations of
MDMA metabolism. Researchers have detected several MDMA metabolites, including
the major metabolite HMMA, and the less abundant metabolites HMA and MDA (De la
Torre et al. 2000; Navarro et al. 2001). Researchers have sought to detect MDMA and
metabolites in blood, urine, sweat and saliva.
Results from current pharmacological studies are similar to those reported in previous
studies, with very few novel findings reported. Four studies, all performed by a team of
researchers in Spain, examined MDMA metabolism in at least two separate samples of
male Ecstasy user volunteers. Two of four reports focused on drug detection, or
detection of drug enantiomers (different versions of the same molecule) (Pizarro et al.
2003; Pichini et al. 2003). One report examined immunological changes after MDMA
given alone, and after three days of pretreatment with the serotonin uptake inhibitor
paroxetine (Pacifici et al. 2004), and one report examined the physiological, subjective,
cognitive, neuroendocrine and pharmacokinetic effects of two doses of 100 mg MDMA
given 24 hours apart (Farre et al. 2004).
Plasma and urine collected from one man given 100 mg MDMA was used to devise a
means of measuring enantiomers of MDMA, and enantiomers of the metabolites MDA,
HMMA, and HMA with gas chromatography-mass spectrometry (GC-MS) (Pizarro et al.
2003). The detection method was successful, and the authors detected both R-(-) and S-
(+) enantiomers of MDMA and metabolites. The R/S ratio of MDMA was opposite that
of MDA in blood and urine, but the R/S ratio for HMMA remained close to 1 (meaning,
there was little difference in amount of each enantiomer) in urine and blood. Pizarro and
colleagues interpreted these findings as evidence that enzymes other than CYP2D6 are
involved in the metabolism of MDMA. The study was not constructed to assess the
involvement of specific enzymes in MDMA metabolism, but the IB and update to the IB
refer to other papers suggesting roles for COMT, CYP1A2, CYP3A4, and other enzymes.
There is little support for the contention that functional differences in CYP2D6 explain
adverse reactions after MDMA (see IB, Kreth 2000; Schwab et al. 1999).
Pichini and colleagues employed a commercially available immunoluminescent assay
(DrugWipe), sweat collection, and the use of gas chromatography with mass
spectrometry (GC-MS) to detect MDMA and metabolites in sweat after 100 mg MDMA
in a sample of 9 men reporting previous Ecstasy use (Pichini et al. 2003). The
researchers also compared their results with results from an earlier study of theirs
assessing MDMA and metabolites in blood and saliva (Navarro et al. 2001). MDMA was
found in the sweat of most subjects, with MDMA first detected 1.5 hours after
administration, though it was only detected 4 hours post-administration in two of nine
participants. The authors found wide intra-subject variability in levels of MDMA
detected in sweat, noting that subjects with higher concentrations of MDMA in sweat
also had the highest concentrations of blood and salivary MDMA. All volunteers
enrolled in this study were extensive CYP2D6 metabolizers, so differences in MDMA
concentration were unrelated to CYP2D6 function. Surprisingly, Pichini and colleagues
were unable to detect HMMA in sweat, despite its greater abundance than HMA or MDA
in blood or urine.
The investigation assessing the role of serotonin release in the immunological effects of
MDMA (100 mg) briefly discusses alterations in MDMA metabolism presumably caused
by three days' pretreatment with 20 mg paroxetine, an SSRI and CYP2D6 inhibitor
(Pacifici et al. 2004). Paroxetine pretreatment increased plasma concentrations of
MDMA (20% Cmax) and 30% increase in AUC). Paroxetine pretreatment increased
levels of unmetabolized MDMA in blood. While these findings are provided in relation
to possible causes of immunological effects, the authors note that higher MDMA levels
would not intensify or increase dose-dependent effects of the drug, because paroxetine
prevents the serotonin transporter from binding to MDMA, thereby preventing serotonin
release.
When compared with an initial dose of 100 mg MDMA, a subsequent dose of the same
amount given 24 hours later produced a 77% increase in plasma MDMA levels, a higher
area under curve (AUC), a measure of drug concentration, and a lower elimination
constant (Farre et al. 2004). Farre and colleagues state that plasma MDMA levels seen
after the second dose were equivalent to those previously associated with 125 mg
MDMA (Mas et al. 1999). Urinary levels of MDMA were also higher after the second
dose of MDMA. MDMA levels after the second dose were higher than expected when
summing any remaining MDMA from the first dose with that of the second dose, a
finding supporting non-linear pharmacokinetics. Extrapolating from these findings, trials
using repeated "booster" doses of MDMA should take into account the effects of non-
linear pharmacokinetics, including greater levels of MDMA than might be expected from
summing remaining levels with the next dose. Making the second dose lower than the
first dose may reduce the risk of unexpected increases in physiological effects of two
closely spaced doses of MDMA. It should be noted that therapists using booster doses
administered them 2 to 4 hours after the initial dose (Greer and Tolbert 1998; Metzner
and Adamson 2001) rather than a day after the first dose.
Though these studies clarify and elaborate on earlier areas of interest in the study of
MDMA pharmacology, to date no recent publication presents findings that contradict
earlier findings reported in the IB or the update to the IB. While great variability across
subjects in detection of MDMA in sweat is notable, all subjects in this study tolerated the
same dose of MDMA (Pichini et al. 2003). Volunteers also tolerated two successive
doses of 100 mg MDMA (Farre et al. 2004). The significance of failing to detect the
major metabolite HMMA in sweat remain unclear, and do not relate to findings relating
to subjective or physiological effects.