HaCKeRz Kr0nlcKLeZ 1/HaCKeRz Kr0nlcKLeZ.iso/drugs/tryptophan.mdma

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Date: Sat, 3 Jul 1993 17:51:36 GMT

                      Arch Gen Psychiatry 1989; 46: 20-22

                                 January, 1989

SECTION: ORIGINAL ARTICLE

LENGTH: 2051 words

TITLE: Neuroendocrine and Mood Responses to Intravenous L-Tryptophan in
3,4-Methylenedioxymethamphetamine ( MDMA)  Users;
Preliminary Observations

AUTHOR: Lawrence H. Price, MD; George A. Ricaurte, MD, PhD; John H. Krystal, MD;
George R. Heninger, MD

ABSTRACT:3,4-Methylenedioxymethamphetamine ( MDMA; "ecstasy" ) is a selective
serotonin (5-HT) neurotoxin in laboratory animals.  To assess its effects on
5-HT function in humans, serum prolactin (PRL) and mood responses to
intravenous L-tryptophan were measured in nine recreational users of MDMA
and compared with findings from nine matched healthy controls.  L-Tryptophan
induced a rise in the PRL concentration in controls, but not in MDMA users.
Peak change and the area under the curve of the PRL response appeared to be
blunted in MDMA users, but the difference from controls did not reach
statistical significance. This study provides suggestive evidence of altered
5-HT function in MDMA users, but more definitive studies clearly are needed.

TEXT:
   A ring-substituted amphetamine derivative,
3,4-methylenedioxymethamphetamine ( MDMA; "ecstasy" ) has serotoninic
effects in the vrains of (5-HT)-selective neurotoxic effects in the brains
of rats [n1-n5] and nonhman primates. [n6,n7] Although classified on
Schedule I by the Drug Enforcement Agency since July 1985, MDMA has become
popular in some settings as a recreational drug.  In an informal survey, up
to 40% of undergraduates at a major university reported having used it at
least once. [n8] Some clinicans have claimed therapeutic utility for MDMA as
an adjunct to psychotherapy, stating that it facilitates interpersonal
communication, enhances insight, and increases selfesteem. [n9]

   We are aware of only one published report on the effects of  MDMA  on 5-HT
function in humans.  Peroutka et al [n10] measured cerebrospinal fluid
levels of the 5-HT metabolite 5-hydroxyindoleacetic acid in five
recreational MDMA users.  They found no significant difference from mean
levels in historical control subjects.  It is possible, of course, that this
sample was too small to detect a difference, or that lumbar cerebrospinal
fluid does not sensitively reflect MDMA -induced changes in central 5-HT
function in humans.


   The neuroendocrine challenge strategy offers a more dynamic means of
assessing central 5-HT function.  Intravenous infusion of the 5-HT precursor
L-tryptophan increases the serum prolactin (PRL) concentration, probably via
enhanced synthesis and release of 5-HT from hypothalamic 5-HT neurons. [n11]
The PRL response to L-tryptophan is blunted in depressed patients compared with
healthy controls, [n12] consistent with other evidence of abnormal 5-HT
function in depression. [n13] May antidepressant drugs, particularly those with
demonstrable effects on 5-HT function, enhance the PRL response. [n14]
Depletion of dietary L-tryptophan also enhances the PRL response, perhaps by a
mechanism analogous to denervation supersensitivity. [n15] In a pilot study, we
compared neuroendocrine and behavioral responses to L-tryptophan in nine heavy
users of  MDMA  with those of matched healthy controls.

SUBJECTS AND METHODS

   Nine subjects (seven male, two female; mean [+/- SD] age, 34 +/- 7 years;
age range, 22 to 47 years) with a current or recent history of substantial
MDMA use volunteered to participate.  They had been using what they believed
to be MDMA for a mean of 5.1 +/- 2.3 years (range, two to seven years) at a
rate of 1.9 +/- 1.7 times per month (range, 0.33 to 5.0 times per month).
The average "usual" dose used was 135 +/- 44 mg (range, 50 to 200 mg),
corresponding to a mean dose of 1.8 +/- 0.4 mg/kg (range, 1.1 to 2.3
mg/kg).  Many subjects reported the occasional use of much higher doses (up
to 500 mg, or 6 mg/kg). The mean cumulative total dose of MDMA was estimated
at 13.3 +/- 13.4g (range, 2.5 to 44.2g).  Nine healthy controls (seven male,
two female; mean age, 33 +/8 years; age range, 22 to 48 years), matched to
the MDMA -using subjects for sex and age, were selected from a larger sample
of normal volunteers who had undergone testing.  Controls were screened for
mental disorder and substance abuse by a research psychiatrist using a
structured review.

   All subjects gave voluntary informed consent and were found to be free of
serious medical illness after physical, neurologic, and laboratory evaluations.
Among  MDMA -using subjects, the last reported use of  MDMA  was a mean of
66+/-50 days before testing (range, 20 to 180 days).  Both control and
 MDMA -using subjects were instructed to remain free of psychoactive drugs for
at least three weeks before testing, although three  MDMA -using subjects
admitted to infrequent marijuana use during that time.  Testing was
conducted on an outpatient basis at the Clinical Neuroscience Research Unit,
New Haven, Conn. Control subjects were recruited locally, but MDMA -using
subjects flew to New Haven from their previous residences the day before
testing.

   Subjects fasted overnight and throughout the three-hour L-tryptophan test,
which began at 9 AM.  The test dose consisted of 7 g of L-trypophan diluted in
500 mL of 0.45% saline solution that was infused through an antecubital vein
catheter over 20 minutes.  Subjects were awake and supine with the head elevated
during the test.  Blood for PRL measurement was obtained through the
indwelling catheter, which was kept patent by the slow infusion of saline
solution. Starting at least 60 minutes after catheter insertion, samples
were obtained at 15 and 0.5 minutes before, and at 30, 40, 50, 60, 70, and
90 minutes after the start of the L-tryptophan infusion.  Visual analog
scales (0 indicates "not at all"; 100 indicates "most ever") and 11
different mood states (happy, sad, drowsy, nervous, calm, depressed,
anxious, energetic, fearful, mellow, high) were scored by subjects at these
times.

   The L-tryptophan infusions were prepared by dissolving 8.4 g of L-tryptophan
in 600 mL_10 of a 0.45% saline solution, with 50% sodium hydroxide added to bring
the solution to a pH of 7.4.  Each 600-mL aliquot was sterilized by passage
through a 0.22-mm filter and tested for pyrogenicity and sterility before use.
Serum was assayed for PRL in control subjects using a radioimmunoassay (RIA)
kit (Serono Diagnostics Inc, Randolph, Mass) with intra-assay and interassay
coefficients of variation of 3% and 7%, respectively.  Because manufacture of
this kit was discontinued, all serum from  MDMA -using subjects was assayed for
PRL with a radioimmunoassay kit (Clinical Assays, Cambridge, Mass), with
intra-assay and interassay coefficients of variation of 6% and 11%,
respectively.  Values obtained with the Serono assay were converted to values
comparable with those obtained with the Clinical Assay kit using a formula
(y=1.99x+14.343; r= .93) that we derived from the testing of 59 specimens with
both kits.

   Data from the -15-minute and -0.5-minute time points were averaged to obtain
a single baseline value for each variable.  The peak change in the PRL level
was determined by subtracting the baseline from the highest PRL value after
L-tryptophan infusion.  The area under the curve (AUC) was calculated for PRL
responses using the trapezoidal rule.  Because of nonnormal distributions,
comparisons of PRL data within and between subjects used the Wilcoxon
signed-rank and Wilcoxon rank-sum tests, respectively.  Mood ratings were
subjected to analysis of variance (ANOVA) with repeated measures.  Correlations
were determined using Spearman's p.  All tests were two-tailed, with
significance set at P< .05.

RESULTS

   The mean (+/-SD) baseline PRL concentration did not differ between
 MDMA -using subjects (9.8+/-5.4 mu g/L) and controls (10.8+/-4.8 mu g/L).
After L-tryptophan infusion the peak increase in the PRL level over baseline
was robustly significant in the controls (11.0+/-13.1 mu g/L; P< .008), but
failed to reach statistical significance in the MDMA users (5.9+/-8.5 mu
g/L; P< .07).  However, the difference in peak change in the PRL
concentration between the two groups was not statistically significant.
There was no correlation between the baseline PRL concentration and peak
change in the PRL concentration in the MDMA group (p=-0.12; not
significant), whereas these variables were significantly correlated in the
controls (p=0.72; P< .03).  The AUC PRL response was also significantly
greater than baseline in the controls (568.8+/-762.5 mu g-min/L; P< .02),
without reaching statistical significance in the MDMA users
(224.8+/-491.9 mu g-min/L; P< .09) (Figure).  Again, the difference between
groups was not significant.  Within the  MDMA  group, baseline PRL and peak PRL
concentrations and the AUC PRL did not correlate with total duration of  MDMA
use, frequency of monthly use, "usual" dose, or estimated cumulative dose.

   As in previous studies, L-tryptophan caused significant decreases in ratings
of energy (F=4.7; df=5,80; P< .001) and happiness (F=3.2; df=5,80; P< .02), and
increases in ratings of drowsiness (F=5.2; df=5,80; P< .0005).  However, there
were no significant differences between diagnostic groups nor were there
differences in group responses to L-tryptophan.

COMMENT

   Results of this exploratory study have suggested some intriguing differences
between  MDMA  users and healthy controls.  The peak change in the PRL
concentration after L-tryptophan administration was 46% lower and the AUC in
the PRL response was 60% lower in MDMA -using subjects than in controls.
Although neither of these differences between groups was statistically
significant, PRL response measures within the control group were
significantly greater than baseline, while those within the MDMA group were
not.  Most subjects in both groups had relatively modest increases in their
PRL concentration after administration of L-tryptophan, as would be expected
in samples composed primarily of men. [n12] However, the MDMA users seemed
less likely to manifest the very marked PRL responses demonstrated by some
healthy subjects, suggesting a degree of blunting in the responsivity of
those subjects ordinarily most sensitive to the effects of L-tryptophan.

   This evidence suggesting altered 5-HT function in  MDMA  users is consistent
with preclinical studies in laboratory animals that have found  MDMA  to have
highly toxic effects on 5-HT neurons.  Such studies have reported  MDMA  to
cause decreased brain levels of 5-HT and 5-hydroxyindoleacetic acid, [n1-n7]
decreased tryptophan hydroxylase activity, [n1] loss of 5-HT uptake sites,
[n2,n5] and degeneration of 5-HT axons and cell bodies. [n3,n6] While large
doses of MDMA (10 to 20 mg/kg) have been required to demonstrate these
effects in rodents, neurotoxicity in monkeys has been observed at doses
comparable with those used by our subjects (2.5 to 5.0 mg/kg). [n6,n7]

   The present findings obviously must be interpreted cautiously.  The
suggested attenuation in the PRL response to L-tryptophan in MDMA users must
be considered in light of the multiple factors known to affect PRL
secretion. [n16] It is also possible that our findings could reflect the
nonspecific stress experienced by MDMA subjects in flying to New Haven on
the day before testing, although our extensive experience with PRL in
neuropsychiatric assessment does not support this hypothesis.

   Our failure to demonstrate more statistically significant effects of  MDMA
probably reflects the small sample size of this study.  Even assuming a large
effect of  MDMA  (standardized difference between group means=0.8), ruling out a
type II error (alpha=0.05; 1-beta=0.80) would require 26 subjects in each
group. In addition to larger samples and more rigorous methodology, other
approaches to assessing 5-HT function in humans might prove more sensitive
to MDMA effects. Such approaches include modification of the standard
L-tryptophan test (eg, use of lower or higher doses of L-tryptophan to
determine if the "threshold" for an increase in PRL is altered), use of
tryptophan depletion techniques, and use of direct 5-HT agonists (eg,
m-chlorophenylpiperazine).  At present, the nature of MDMA's effects on 5-HT
function in humans is unknown and the alteration in function suggested by
the results of this study cannot be considered established.  The potential
for 5-HT neurotoxicity in humans is a pressing concern, however, and the
development of sensitive and reliable tests for assessing this remains a
challenge.

SUPPLEMENTARY INFORMATION: Accepted for publication Oct 19, 1988.

   From the Department of Psychiatry, Yale University School of Medicine, and
the Connecticut Mental Health Center, Clinical Neuroscience Research Unit,
Ribicoff Research Facilities, New Haven, Conn (Drs Price, Krystal, and
Heninger); and the Department of Neurology, The Johns Hopkins University School
of Medicine, Baltimore (Dr Ricaurte).

   Reprint requests to Department of Psychiatry, Yale University School of
Medicine, and the Connecticut Mental Health Center, Clinical Neuroscience
Research Unit, Ribicoff Research Facilities, 34 Park St, New Haven, CN 06508
(Dr Price).

   This study was supported in part by grants MH-00579, MH-36229, MH25642, and
DA-04060 from the US Public Health Service, Washington, DC; by the
Multidisciplinary Association for Psychedelic Studies, Sarasota, Fla; and by the
state of Connecticut.

   Daniel X. Freedman, MD, was instrumental in facilitating the collaboration.
The laboratory, clinical, and research staffs of the Abraham Ribicoff Research
Facilities, New Haven, Conn, provided assistance.  Huan Gao, MA, assisted in
the data analysis and Evelyn Testa typed the manuscript.

REFERENCES:

[n1.] Stone DM, Stahl DC, Hanson GR, Gibb JW: The effects of
3,4-methylenedioxymethamphetamine ( MDMA)  and 3,4-methylenedioxyamphetamine
(MDA) on monoaminergic systems in the rat brain.  Eur J Pharmacol
1986;128:41-48.

[n2.] Battaglia G, Yeh SY, O'Hearn, Molliver ME, Kuhar MJ, DeSouza EB:
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy
serotonin terminals in rat brain: Quantification of neurodegeneration by
measurement of [<3>H] paroxetine-labeled serotonin uptake sites.  J Pharmacol
Exp Ther 1987;242:911-916.

[n3.] Commins DL, Vosmer G, Virus RM, Woolverton WL, Schuster CR, Seiden LS:
Biochemical and histological evidence that methylenedioxymethylamphetamine
( MDMA)  is toxic to neurons in the rat brain.  J Pharmacol Exp Ther
1987;241:338-345.

[n4.] Mokler DJ, Robinson SE, Rosecrans JA: (+/-)
3,4-Methylenedioxymethamphetamine ( MDMA)  produces long-term reductions in
brain 5-hydroxytryptamine in rats.  Eur J Pharmacol 1987;138:265-268.

[n5.] Schmidt CJ: Neurotoxicity of the psychedelic amphetamine,
methylenedioxymethamphetamine.  J Pharmacol Exp Ther 1987;240:1-7.

[n6.] Ricaurte GA, Forno LS, Wilson MA, DeLanney LE, Irwin I, Molliver ME,
Langston JW: (+/-) 3,4-Methylenedioxymethamphetamine selectively damages
central serotonergic neurons in nonhuman primates.  JAMA 1988;260:51-55

[n7.] Ricaurte GA, DeLanney LE, Irwin I, Langston JW: Toxic effects of MDMA
on central serotonergic neurons in the primate: Importance of route and
frequency of drug administration.  Brain Res 1988;446:165-168.

[n8.] Peroutka SJ: Incidence of recreational use of
3,4-methylenedioxymethamphetamine ( MDMA, 'ecstasy' ) on an undergraduate
campus.  N Engl J Med 1987;317:1542-1543.

[n9.] Greer G, Tolbert R: Subjective reports on the effects of  MDMA  in a
clinical setting.  J Psychoactive Drugs 1986;18:319-327.

[n10.] Peroutka SJ, Pascoe N, Faull KF: Monoamine metabolites in the
cerebrospinal fluid of recreational users of 3,4-methylenedioxymethamphetamine
( MDMA; 'ecstasy' ).  Res Commun Drug Abuse 1987;8:125-138.

[n11.] Charney DS, Heninger GR, Reinhard JF Jr, Sternberg DE, Hafstead KM: The
effect of IV L-tryptophan on prolactin, growth hormone, and mood in healthy
subjects.  Psychopharmacology 1982;78:38-43.

[n12.] Heninger GR, Charney DS, Sternberg DE: Serotonergic function in
depression: Prolactin response to intravenous tryptophan in depressed patients
and healthy subjects.  Arch Gen Psychiatry 1984;41:398-402.

[n13.] Meltzer HY, Lowy MT: The serotonin hypothesis of depression, in Meltzer
HY (ed): Psychopharmacology: The Third Generation of Progress. New York, Raven
Press, 1987, pp 513-526.


[n14.] Price LH, Charney DS, Delgado PL, Heninger GR: Lithium treatment and
serotonergic function: Neuroendocrine and behavioral responses to intravenous
L-tryptophan in affective disorder patients.  Arch Gen Psychiatry
1989;46:13-19.

[n15.] Gelgado PL, Charney DS, Price LH, Anderson G, Landis H, Heninger GR:
Dietary tryptophan restriction produces an upregulation of the neuroendocrine
response to infused tryptophan in healthy subjects.  Soc Neurosci Abstr
1987;13:227.

[n16.] McCann SM: Lumpkin MD, Mizunuma H, Khorram O, Ottlecz A, Samson WK:
Peptidergic and dopaminergic control of prolactin release.  Trends Neurosci
1984;5:127-131.

GRAPHIC: Figure, Mean (+/-SEM) prolactin response over time to intravenous
L-tryptophan in nine 3,4-methylenedioxymethamphetamine users and nine healthy
controls.
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