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GYNÆCOLOGICAL SIDE-EFFECTS OF LEVODOPA THERAPY
807
L-TRYPTOPHAN AS A PHYSIOLOGICAL HYPNOTIC
SIR,-I am happy that Wyatt et al.agree with our suggestion 2,3 that L-tryptophan may be a physiological hypnotic " or natural sedative ". Our data in man and in the rat demonstrate that L-tryptophan (4-10 g. in man, 300-600 mg. per kg. in the rat) produces a significant reduction in sleep latency with little change in sleep stages or cycling.2-5 Overall, sleep latency was reduced from a mean value of 17-1 minutes on placebo to a mean of 9-8 minutes on L-tryptophan in 103 all-night polygraphic recordings in nine normal people (p < 0-01). Mean sleep latency was reduced from 11-1minutes to 5-6 minutes in 55 polygraphic recordings in 11 rats (P<0’01). Sleep latency was also reduced by L-tryptophan as opposed to placebo significantly in 24 insomniac patients studied by behavioural rather than E.E.G. measures. However, I find questionable the suggestion of Wyatt et al. that the sedative effect of L-tryptophan does not involve the serotonin pathway. They argue first of all that, since agents such as pchlorophenylalanine (pC.P.A.) which lower brain serotonin levels produce a decrease in desynchronised or rapid-eyemovement sleep (D) in man which can be restored by 5-hydroxytryptophan, serotonin has an enhancing effect on D-time. Since they find a decreased D-time after L-tryptophan, they conclude that it is not acting through serotonin. However, the decrease in D-time which they report is only 20%; other studies have disclosed no effect or a slight increase in D-time with similar doses of L-tryptophan, 4,6 and Williamshas lately suggested that larger doses may produce a sharp increase. Therefore the exact effect of L-tryptophan on D-time must be considered an unsettled question. And, in any case, the effect of L-tryptophan on D-time and its sedative effect may involve entirely different pathways, so that the effects on D-time may not be relevant "
"
to
intake rather than to an improbable but frequently postulated hxmodynamic shift-" blood leaves the brain and goes to the gut ". From the clinical standpoint, considering that available sleeping medications are basically general anaesthetics taken in small doses, there might well be advantages to the use of a hypnotic such as L-tryptophan; my laboratory has started some clinical trials with encouraging early results. Sleep and Dream Laboratory, Boston State Hospital, Boston, Mass. 02124.
ERNEST HARTMANN.
GYNÆCOLOGICAL SIDE-EFFECTS OF LEVODOPA THERAPY of
postmenopausal vaginal bleeding during levodopa therapy, reported by Dr. KruseLarsen and Dr. Garde (April 3, p. 707), has in fact been observed previously.! Indeed, some such side-effect had even been predicted on theoretical grounds, for dopa SiR,—The
occurrence
the female rat, like that of progesterone, aopears provoke a specific increase in uterine monoamine oxidase (M.A.C.) activity 3; pronounced increases in M.A.o. activity have been noted in human endometrium in the late secretory phase of the menstrual cycle,4 a possible but undetermined factor in the onset of menstruation. Future
administration
to
to
observations
particularly patient, may
gynaecological sequelae of levodopa therapy, in the rare, premenopausal parkinsonian thus add to our knowledge of the menstrual
on
process. Queen Charlotte’s Maternity Hospital, London W.6.
M. SANDLER.
the sedative effect.
Further, Wyatt et al. argue that in three patients undergoing chronic pC.P.A. administration, L-tryptophan had the same effect as in untreated normals, and therefore the serotonin pathway (blocked by pC.P.A.) cannot be involved. Again, there are two objections. First, the chief " unchanged " effect they refer to is the decrease in D-time, but it is far from clear that this effect is unchanged. As mentioned, the effect in normal individuals is not settled; even Wyatt et al. found only a slight decrease. After pC.P.A. they show a 50% decrease. Secondly, an effect on D-time is not the same as sedative effect. If the prominent sedative effect of L-tryptophan, as measured by a reduced sleep latency, were still clearly present in the patients receiving pC.P.A., this would be a strong argument for these workers’ thesis. However, sleep latency in these patients is not mentioned, so one must assume that the results were at best equivocal. I therefore suggest that the serotonin pathway has not been excluded, and that we do not yet know for certain how L-tryptophan exerts its sedative effect. Since L-tryptophan in doses of 4 to 10 g. has such a strong sedative property, and since 0-5-2 g. is ingested in the normal daily diet, L-tryptophan may well play a role in normal tiredness and sleep induction. I have suggested that drowsiness after a large meal may be related to L-tryptophan 1. 2. 3.
4. 5.
6. 7.
Wyatt, R. J., Engleman, K., Kupfer, D. J., Fram, D. H., Sjoerdsma, A., Snyder, F. Lancet, 1970, ii, 842. Hartmann, E. Psychophysiology, 1970, 7, 320 (abstr.). Hartmann, E., Chung, R., Chien, C. Psychopharmacologia, 1971, 19, 114. Hartmann, E. Psychonom. Sci. 1967, 8, 479. Hartmann, E., Chung, R. Report to be presented to the Association for the Psychophysiological Study of Sleep, Bruges, Belgium, June, 1971. Williams, H. L., Lester, B. K., Coulter, J. D. Activitas nerv. sup. 1969, 11, 188. Williams, H. L. Personal communication.
ADRENAL FUNCTION TESTED WITH TETRACOSACTRIN DEPOT
SIR,-In relation to the paper by Dr. Galvao-Teles and his co-workers concerning the use of tetracosactrin depot in testing adrenal function (March 20, p. 557) we wish to report that we have been using this test for the past 3 years. Studying the effect of tetracosactrin depot (’ Depot-Synacthen ’) on adrenal function, we too found that the greatest 6 response occurred 6 hours after intramuscular injection. We have applied this " 6-hour intramuscular depotsynacthen plasma corticoid test " in many cases of Addison’s disease, Cushing’s syndrome, and secondary adrenal cortical insufficiency due to steroid treatment or to hypopituitarism. Our results were similar to those of Dr. Galvao-Teles and his co-workers. We are very satisfied with this test, especially for investigation of secondary adrenal cortical insufficiency in which the 0-25 mg. ordinary synacthen test was not satisfactory. In patients with Addison’s disease and with secondary adrenal atrophy the intramuscular depot-synacthen test is done on 3 consecutive days. Blood specimens for plasmacortisol levels are drawn before and 6 hours after the first injection, and 6 hours after the third injection of this
synthetic corticotrophin. We wish to point out that this synthetic polypeptide in Ansel, R. D. in L-dopa and Parkinsonism (edited by A. Barbeau and F. H. McDowell); p. 317. Philadelphia, 1970. 2. Sandler, M. ibid. p. 317. 3. Collins, G. G. S., Pryse-Davies, J., Sandler, M., Southgate, J. Nature, 1970, 226, 642. 4. Southgate, J., Grant, E. C. G., Pollard, W., Pryse-Davies, J., Sandler, M. Biochem. Pharmac. 1968, 17, 721. 5. Cohen, S., Bitensky, L., Chayen, J., Cunningham, G. J., Russell, J. K. Lancet, 1964, ii, 56. 6. Benos, S. A., Koutsoukos, A., Braouzi, H., Georgopoulos, A., Pavlatos, F.Ch. Acta allerg. 1969, 24, 165. 1.
L-TRYPTOPHAN AS A PHYSIOLOGICAL HYPNOTIC
SIR,-I am happy that Wyatt et al.agree with our suggestion 2,3 that L-tryptophan may be a physiological hypnotic " or natural sedative ". Our data in man and in the rat demonstrate that L-tryptophan (4-10 g. in man, 300-600 mg. per kg. in the rat) produces a significant reduction in sleep latency with little change in sleep stages or cycling.2-5 Overall, sleep latency was reduced from a mean value of 17-1 minutes on placebo to a mean of 9-8 minutes on L-tryptophan in 103 all-night polygraphic recordings in nine normal people (p < 0-01). Mean sleep latency was reduced from 11-1minutes to 5-6 minutes in 55 polygraphic recordings in 11 rats (P<0’01). Sleep latency was also reduced by L-tryptophan as opposed to placebo significantly in 24 insomniac patients studied by behavioural rather than E.E.G. measures. However, I find questionable the suggestion of Wyatt et al. that the sedative effect of L-tryptophan does not involve the serotonin pathway. They argue first of all that, since agents such as pchlorophenylalanine (pC.P.A.) which lower brain serotonin levels produce a decrease in desynchronised or rapid-eyemovement sleep (D) in man which can be restored by 5-hydroxytryptophan, serotonin has an enhancing effect on D-time. Since they find a decreased D-time after L-tryptophan, they conclude that it is not acting through serotonin. However, the decrease in D-time which they report is only 20%; other studies have disclosed no effect or a slight increase in D-time with similar doses of L-tryptophan, 4,6 and Williamshas lately suggested that larger doses may produce a sharp increase. Therefore the exact effect of L-tryptophan on D-time must be considered an unsettled question. And, in any case, the effect of L-tryptophan on D-time and its sedative effect may involve entirely different pathways, so that the effects on D-time may not be relevant "
"
to
intake rather than to an improbable but frequently postulated hxmodynamic shift-" blood leaves the brain and goes to the gut ". From the clinical standpoint, considering that available sleeping medications are basically general anaesthetics taken in small doses, there might well be advantages to the use of a hypnotic such as L-tryptophan; my laboratory has started some clinical trials with encouraging early results. Sleep and Dream Laboratory, Boston State Hospital, Boston, Mass. 02124.
ERNEST HARTMANN.
GYNÆCOLOGICAL SIDE-EFFECTS OF LEVODOPA THERAPY of
postmenopausal vaginal bleeding during levodopa therapy, reported by Dr. KruseLarsen and Dr. Garde (April 3, p. 707), has in fact been observed previously.! Indeed, some such side-effect had even been predicted on theoretical grounds, for dopa SiR,—The
occurrence
the female rat, like that of progesterone, aopears provoke a specific increase in uterine monoamine oxidase (M.A.C.) activity 3; pronounced increases in M.A.o. activity have been noted in human endometrium in the late secretory phase of the menstrual cycle,4 a possible but undetermined factor in the onset of menstruation. Future
administration
to
to
observations
particularly patient, may
gynaecological sequelae of levodopa therapy, in the rare, premenopausal parkinsonian thus add to our knowledge of the menstrual
on
process. Queen Charlotte’s Maternity Hospital, London W.6.
M. SANDLER.
the sedative effect.
Further, Wyatt et al. argue that in three patients undergoing chronic pC.P.A. administration, L-tryptophan had the same effect as in untreated normals, and therefore the serotonin pathway (blocked by pC.P.A.) cannot be involved. Again, there are two objections. First, the chief " unchanged " effect they refer to is the decrease in D-time, but it is far from clear that this effect is unchanged. As mentioned, the effect in normal individuals is not settled; even Wyatt et al. found only a slight decrease. After pC.P.A. they show a 50% decrease. Secondly, an effect on D-time is not the same as sedative effect. If the prominent sedative effect of L-tryptophan, as measured by a reduced sleep latency, were still clearly present in the patients receiving pC.P.A., this would be a strong argument for these workers’ thesis. However, sleep latency in these patients is not mentioned, so one must assume that the results were at best equivocal. I therefore suggest that the serotonin pathway has not been excluded, and that we do not yet know for certain how L-tryptophan exerts its sedative effect. Since L-tryptophan in doses of 4 to 10 g. has such a strong sedative property, and since 0-5-2 g. is ingested in the normal daily diet, L-tryptophan may well play a role in normal tiredness and sleep induction. I have suggested that drowsiness after a large meal may be related to L-tryptophan 1. 2. 3.
4. 5.
6. 7.
Wyatt, R. J., Engleman, K., Kupfer, D. J., Fram, D. H., Sjoerdsma, A., Snyder, F. Lancet, 1970, ii, 842. Hartmann, E. Psychophysiology, 1970, 7, 320 (abstr.). Hartmann, E., Chung, R., Chien, C. Psychopharmacologia, 1971, 19, 114. Hartmann, E. Psychonom. Sci. 1967, 8, 479. Hartmann, E., Chung, R. Report to be presented to the Association for the Psychophysiological Study of Sleep, Bruges, Belgium, June, 1971. Williams, H. L., Lester, B. K., Coulter, J. D. Activitas nerv. sup. 1969, 11, 188. Williams, H. L. Personal communication.
ADRENAL FUNCTION TESTED WITH TETRACOSACTRIN DEPOT
SIR,-In relation to the paper by Dr. Galvao-Teles and his co-workers concerning the use of tetracosactrin depot in testing adrenal function (March 20, p. 557) we wish to report that we have been using this test for the past 3 years. Studying the effect of tetracosactrin depot (’ Depot-Synacthen ’) on adrenal function, we too found that the greatest 6 response occurred 6 hours after intramuscular injection. We have applied this " 6-hour intramuscular depotsynacthen plasma corticoid test " in many cases of Addison’s disease, Cushing’s syndrome, and secondary adrenal cortical insufficiency due to steroid treatment or to hypopituitarism. Our results were similar to those of Dr. Galvao-Teles and his co-workers. We are very satisfied with this test, especially for investigation of secondary adrenal cortical insufficiency in which the 0-25 mg. ordinary synacthen test was not satisfactory. In patients with Addison’s disease and with secondary adrenal atrophy the intramuscular depot-synacthen test is done on 3 consecutive days. Blood specimens for plasmacortisol levels are drawn before and 6 hours after the first injection, and 6 hours after the third injection of this
synthetic corticotrophin. We wish to point out that this synthetic polypeptide in Ansel, R. D. in L-dopa and Parkinsonism (edited by A. Barbeau and F. H. McDowell); p. 317. Philadelphia, 1970. 2. Sandler, M. ibid. p. 317. 3. Collins, G. G. S., Pryse-Davies, J., Sandler, M., Southgate, J. Nature, 1970, 226, 642. 4. Southgate, J., Grant, E. C. G., Pollard, W., Pryse-Davies, J., Sandler, M. Biochem. Pharmac. 1968, 17, 721. 5. Cohen, S., Bitensky, L., Chayen, J., Cunningham, G. J., Russell, J. K. Lancet, 1964, ii, 56. 6. Benos, S. A., Koutsoukos, A., Braouzi, H., Georgopoulos, A., Pavlatos, F.Ch. Acta allerg. 1969, 24, 165. 1.