Matthew Baggott (matt@baggott.net) If you've ever been to LA and you picture it in your mind, you just need to add some New York and Latin American accents and you've got Miami, Florida. As a fog-addled denizen of the San Francisco Bay Area, fond as I am of hot coffee and democracy, it took a science conference to bring me to the Sunshine State. And what a conference. The annual meeting of the College on Problems of Drug Dependence is the conference for seeing and showing results relating to research on illicit drug use. And this year's conference was rich with preliminary results from studies of MDMA. Choosing which of the many MDMA presentations I should summarize in this limited space was difficult. Here are just a few of the many interesting studies. M. Tancer of Wayne State University in Detroit presented data from the first few volunteers in an ongoing study of the effects of ambient temperature on people on MDMA. Healthy volunteers were given 2.0 mg/kg MDMA (about 140 mg, probably similar to one-and-a-half or two ecstasy pills) or placebo. So far, it looks like you get similar small body temperature increases from taking 2.0 mg/MDMA in a cold (18¡C, or 64¡F) room as in a warmer (30¡C/86¡F) room. Assuming subsequent volunteers show the same pattern, this suggests moderate doses of MDMA do not produce the difficulty regulating body temperature seen in several studies of rats were given MDMA. One possible explanation is that humans are less vulnerable to body temperature changes than rats because humans can remove any fur we are wearing, can sweat, and have high surface-to-volume ratios.
"The annual meeting of the College
on Problems of Drug Dependence is
the conference for seeing and
showing results relating to research
on illicit drug use."
However, it is also possible that the dose of MDMA was too low to derange body temperature
aside from a slight rise due to vasoconstriction. In a rat study, Dafters (1994) found that 2.5
mg/kg MDMA produced an apparent similar rise in temperature in either warm (29¡C/84¡F) or cold
(11¡C/52¡F) settings. Higher doses of 5.0 or 7.5 mg/kg were needed to make the animals become
cold in the cold setting or hot in the normal setting. The importance of all this research is that
increased body temperature can strain the body, possibly increasing risk of toxicity. Many deaths
and serious adverse events in ecstasy users involve high (> 38¡C/100¡F) body temperature and we
don't really know how much these cases are due to putative risk factors like too much dancing and
too little water. So far, Tancer's ongoing
study seems likely to confirm that
moderate doses of MDMA do not impair
regulation of body temperature in
most people and that humans are not
more sensitive than rats to this drug
effect.
P.Y. Bello and several other collaborators from the French Monitoring Centre on Drugs and Drug Abuse described results from a large French drug analysis program called SINTES (Systeme National d'Identification des Toxiques et Substances). The program obtains samples from both social/health workers and law enforcement and analyzes them with GC/MS and HPLC techniques. Of 1369 samples obtained from social/ health workers, 97% were thought by submitters to contain MDMA. In reality, 83% contained MDMA and 5% contained amphetamines or MDMA-like compounds.
"So far, Tancer's ongoing
study seems likely to confirm
that moderate doses of MDMA
do not impair regulation of
body temperature in most
people and that humans are
not more sensitive than rats
to this drug effect."
There was wide variability in doses with only 2% of MDMA pills
containing more than 100 mg MDMA. Average
dose per pill appeared
to be decreasing over
time. Samples contained
74 +/- 18 mg
MDMA in 2000, 63 +/-
14 mg MDMA in 2001,
and 58 +/- 13 mg
MDMA in 2002. If this
trend is true in other
European countries, it
may have important
implications for understanding
studies of ecstasy
users, who often
seem to be taking
more tablets than appeared common several
years ago. More information of the SINTES program
can be found on their website: http://www.ofdt.fr/BDD/sintes.
R.V. Irvine from the University of Adelaide, Australia presented preliminary data from an ongoing study measuring MDMA concentrations, biological changes, and physical changes in 24 ecstasy users before, during, and/or after a rave. Blood samples taken after the rave showed plasma concentrations of MDMA that were often around 0.3 mg/L MDMA. However, several participants had plasma concentrations that were above 0.75 mg/L MDMA. Previously, levels this high have only been documented in emergency medicine settings. These high drug levels are even more impressive when one considers they were seen the morning after the rave and that peak plasma concentrations may have been approximately twice as high. Heart rate and blood pressure were elevated in the morning, although not to a degree that would be inherently dangerous in a healthy individual. MDMA plasma concentrations were significantly correlated with body temperature (measured using the tympanic membrane in the ear), which was at or above 38¼C in two participants during morning measurements. Obviously, exercise may have contributed to all these physiological changes. These data suggest that at least some experienced users can tolerate high MDMA concentrations without clinically significant changes in physiology and that other factors such as drug combinations, behavioral or environmental conditions may be important in precipitating the acute adverse event seen in some users. R. de la Torre of the Institut Municipal d'Investigaci—n MŽdica in Barcelona gave a comprehensive overview of the work he and his colleagues at the Universitat Autonoma de Barcelona have been conducting on the human pharmacology of MDMA. Recent studies have explored the effects of giving two doses of 100 mg MDMA, either four or twenty-four hours apart. Even though people notice fewer effects from the second dose than the first, the second dose is less metabolized than the first. As a result, MDMA exposures (measured as the area under the drug concentration vs. time curve) are about 20 to 30% higher after the second 100 mg MDMA dose than you would expect based on the first. There is less formation of at least one metabolite, 4-hydroxy-3-methoxy-methamphetamine, which suggests that liver enzymes were inhibited by the first MDMA dose.
"Because DEA generally seizes
compounds in the course of
fighting trafficking of scheduled
drugs...this suggests that
unscheduled compounds are more
likely to become scheduled if
unscrupulous people sell
them as 'ecstasy'."
Previous
studies (e.g.
Delaforge et al.
1999) using liver
tissue have indicated
that MDMA
inhibits an enzyme
called CYP2D6
(which is short for
"cytochrome P450 isozyme 2D6"). De la Torre's
presentation suggests this inhibition of CPY2D6
lasts more than 24 hrs after MDMA, which means
people may have altered metabolism of some
drugs (such as codeine) the day after MDMA.
Because CYP2D6 is inhibited after MDMA, the
enzyme appears less important in MDMA metabolism
than researchers once thought. People
with low CYP2D6 activity (about 10% of Caucasians
are like this due to genetics) thus no longer
seem likely to be at significantly increased risk
of acute adverse events after MDMA (see also:
Gilhooly & Daly 2002; O'Donohoe et al. 1998;
Schwab et al. 1999). (How CYP2D6 activity influences
risks of chronic toxicity remains difficult
to assess.)
E. Tella of the Drug Enforcement Administration had a poster presentation summarizing his agency's concerns with the research chemicals AMT (alpha-methyl-tryptamine), 5-MeO-DIPT (5-methoxy-dipropyltryptamine) and the combination of BZP (benzylpiperazine) and TFMPP (3-trifluoromethylphenylpiperazine). He indicated that, in addition to emergency department visits and deaths, drug seizures are an important indicator the agency uses in assessing which research chemicals are significant problems. Because the agency generally seizes compounds in the course of fighting trafficking of scheduled drugs (like MDMA), this suggests that unscheduled compounds are more likely to become scheduled if unscrupulous people sell them as "ecstasy". All in all it was an interesting conference. Of course, like most conferences, the real action was the informal schmoozing in the halls. I heard about a lot of interesting findings and rumors. I hope that some of these data actually get presented at next year's conference. References Dafters, R.I., Effect of ambient temperature on hyperthermia and hyperkinesis induced by 3,4- methylenedioxymethamphetamine (MDMA or "ecstasy") in rats. Psychopharmacology (Berl), 1994. 114(3): p. 505-8. Delaforge, M., M. Jaouen, and G. Bouille, Inhibitory metabolite complex formation of methylenedioxy-methamphetamine with rat and human cytochrome p450: particular involvement of CYP 2D. Environmental Toxicology and Pharmacology, 1999. 7: p. 7:153-158. Gilhooly, T.C. and A.K. Daly, CYP2D6 deficiency, a factor in ecstasy related deaths? Br J Clin Pharmacol, 2002. 54(1): p. 69-70. O'Donohoe, A., K. O'Flynn, K. Shields, Z. Hawi, and M. Gill, MDMA toxicity: no evidence for a major influence of metabolic genotype at CYP2D6. Addiction Biology, 1998. 3: p. 309-314. Schwab, M., E. Seyringer, R.B. Brauer, A. Hellinger, and E.U. Griese, Fatal MDMA intoxication. Lancet, 1999. 353(9152): p. 593-4
Matthew Baggott is a Research Associate at California
Pacific Medical Center, and graduate student
in neuroscience at University of California,
Berkeley
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