MAPS: Reneman et al: Ecstasy + amphetamine =?

[Alex Gamma <gamma@xxxxxxxxxxxx>]

Dear forum, dear Liesbeth,

Dutch researchers Reneman and colleagues have recently reported on the
effects of concomitant use of Ecstasy and amphetamine on striatal dopamine
(DA) transporter binding (abstract below). Their interpretation of the data
can be found already in the title of the paper: "Use of amphetamine by
recreational users of ecstasy (MDMA) is associated with reduced striatal
dopamine transporter densities..."

As usual, Reneman et al is to be commended for presenting interesting data
using methods that have not been used in the field of Ecstasy research -
like, in this case, beta-CIT SPECT scans for measuring DA transporters.
In short, the study included 9 heavy Ecstasy+amphetamine users, 29 heavy
Ecstasy (but not intentional amphetamine) users and 15 Ecstasy-naive
controls. All users were drug-abstinent for at least 3 weeks. SPECT scans
revealed 3 main findings:

1) Ecstasy users had *higher* DA transporter densities than controls
2) There was no difference in DA transporter densities between
Ecstasy+amphetamine users and controls
3) Ecstasy+amphetamine users had *lower* DA transporter densities than
Ecstasy users.

While these data are highly interesting, I have problems with how Reneman et
al interpret them. The title of their paper uses the term "reduced ...
transporter densities" without specifying any reference, i.e. compared to
*what* transporter densisites were reduced. As such, the title naturally
implies that additional amphetamine use in Ecstasy users leads to a
reduction of DA transporters below normal levels (i.e. below levels of
controls). But, this is not the case (see finding 2). A similar sentence
appears in the discussion ("...the combined use of amphtamine and ecstasy
may be assciated with reduced striatal DA transporter densities"), again
without specifying a reference. This (deliberately?) loose wording implies
sub-normal DA transporter levels, and thus seems to indicate some kind of
damage or abnormality.

Another, more serious overinterpretation lies in the final passage of the
discussion. There it says: "...the reported use of amphetamine in regular
ecstasy users seems to be associated with toxic damage to dopaminergic
neurones..."

I think this conclusion is not justified by the results. The results show
that "pure" Ecstasy users have higher DA transporter levels than controls,
which, as Reneman et al point out, may reflect up-regulation of DA
transporters induced by blockade of serotonin uptake. However, since
combined Ecstasy+amphetamine users have normal DA transporter levels, it
appears that the additional use of amphetamine somehow counteracts and
cancels out the DA transporter increase induced by Ecstasy.

Now Reneman and colleagues conclude that this counter-action is some kind of
neurotoxic damage to dopaminergic neurons. This certainly is one
possibility. But the authors completely ignore the possibility that
amphetamine leads to a non-neurotoxic down-regulation of DA transporters,
which cancels out the up-regulation induced by Ecstasy/MDMA.

Again, the impression one gets is that the authors want to emphasize the
potential dangers of drug use at the expense of a balanced interpretatin of
their results.

Finally, I can't help wondering how careful in general the discussion of
this paper was prepared. One finds two remarkable sentences towards the end
of the discussion, which have left me rather puzzled:

"People with low DA transporter densities may be predisposed to use
amphetamine and to have low DA transporter densities."

"However, the two groups of amphetamine users were both regular users of
ecstasy and differed only on the point that one subgroup had a history of
amphetamine use."

There are 8 authors in this paper (and a number of reviewers), and none of
them noticed these strange statements. Allow me to entertain the speculation
that the authors must have been in a terrible hurry putting this paper out.


To end on a more  positive note, one should mention that Reneman and
colleagues, in the discussion section, help dismantling the myth of
"Ecstasy-induced parkinsonism".

Alex

**********************

Psychopharmacology (Berl) 2002 Jan;159(3):335-340

Use of amphetamine by recreational users of ecstasy (MDMA) is associated
with reduced striatal dopamine transporter densities: a [(123)I]beta-CIT
SPECT study -- preliminary report.

Reneman L, Booij J, Lavalaye J, de Bruin K, Reitsma JB, Gunning B, den
Heeten GJ, van Den Brink W.

Department of Nuclear Medicine, Academic Medical Center, Meibergdreef 9,
1105 AZ Amsterdam, The Netherlands,l.reneman@xxxxxxxxxx

RATIONALE: Tablets sold as ecstasy often contain not only
3,4-methylenedioxymethamphetamine (MDMA) but other compounds well known to
cause dopaminergic neurotoxicity, such as (meth)amphetamine. Furthermore,
the use of ecstasy in the Netherlands is often combined with the use of
amphetamine. However, little is known about the effects of ecstasy use or
the combination of ecstasy and amphetamine use on dopamine (DA) neurones in
the human brain. OBJECTIVES: This study was designed to investigate the
effects of ecstasy as well as the combined use of ecstasy and amphetamine on
the density of nigrostriatal DA neurones. METHODS: [(123)I]beta-CIT SPECT
was used to quantify striatal DA transporters. Striatal [(123)I]beta-CIT
binding ratios of control subjects ( n=15) were compared with binding ratios
of ecstasy users ( n=29) and individuals with a history of combined ecstasy
and amphetamine use ( n=9) after adjustment for age. RESULTS: Striatal
[(123)I]beta-CIT binding ratios were significantly lower in combined ecstasy
and amphetamine users compared to sole ecstasy users (6.75 versus 8.46,
respectively: -20.2%, P=0.007). Binding ratios were significantly higher in
ecstasy users when compared to controls (8.46 versus 7.47, respectively:
+13.2%, P=0.045). CONCLUSIONS: These initial observations suggest that the
sole use of ecstasy is not related to dopaminergic neurotoxicity in humans.
In contrast, the reported use of amphetamine by regular users of ecstasy
seems to be associated with a reduction in nigrostriatal DA neurones.

*****************************

-- 

Alex Gamma, PhD
University Hospital of Psychiatry
Research Department
Lenggstr. 31
8029 Zurich
Switzerland

email: gamma@xxxxxxxxxxxx
Phone: +41 1 384 26 35
Fax: +41 1 384 33 96


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