- Email: [email protected]
One gram of l -tryptophan fails to alter the time taken to fall asleep
ONE
CRAM THE
OF L-TRYPTOP~AN TIME
TAKEN
TO
FAILS TO ALTER FALL
ASLEEP
KIRSTNE ADAM and I. OSWALD liniversity Dept Psychiatry, Morningside Park, Edinburgh EHIO SHF, U.K.
It has been claimed by Hartmann and his colleagues that 1 g of t-tryptophan, taken 20min prior to retiring will shorten the deiay to the onset of sleep. In the first publication in which this was claimed (Hartmann, Cravens and List, 1974), 10 normal subjects aged 21--35 yr were used and seven different doses, between 1 and 15 g tryptophan or placebo alone, were used on different nights. Full details of the design are not given but it is obvious that the order of presentation could not have been balanced. In the evaluation, multiple t-tests were used; this is an invalid procedure as sleep latencies do not fall into a normal distribution. In defining the onset of sleep, stage 1 sleep was used, contrary to usual international practice, whereby sleep onset is taken as the first stage 2 sleep, with EECi sleep spindles (Rechtscha~en and Kales, 19613).Stage 1 is hard to define and when people are falling asleep stage 1 (drowsiness) comes and goes for a few seconds at a time, many times over. In a subsequent paper (Hartmann and Elion, 19773, 42 normal college students were used. They were not used as their own controls and 14 who took placebo at bedtime were compared with 14 who took L-tryptophan 1 g. A significant difference between tryptophan 1 g and placebo was claimed but once again there can be criticisms as there is no mention of prior matching of these groups for the length of time they usually took to fall asleep and there is no information about the time when they were put to bed in relation to their normal time of going to bed.
There were four experimental nights. On all these nights the subjects took two pills 20 min before lightsout. On two nights the pills were inert and on two nights contained a total of 1 g of L-tryptophan. In addition, subjects varied their evening diets according to a planned design, such that when they had their evening meal, at the customary time (always before 2O:OOhr), they ate a low carbohydrate meal on two of the experimental nights and a high carbohydrate meal on the other two nights. The design was such that there was balance among all four conditions, so that four subjects would have, where P = placebo, H = high T = tryptophan, carbohydrate and L = low carbohydrate:
,METHODS
The agreement of the Royal Edinburgh Hospital Ethics Committee was obtained. Initially subjects aged 35-65 yr were enrolled if they reported taking a long time to fall asleep and were given four preliminary nights in the sleep laboratory. On all nights full laboratory procedures were used but recordings were only made on the third and fourth nights. Subjects were accepted into the study only if the latency to stage 2 sleep on the third and fourth nights averaged over 25 min. Twelve subjects of mean age 54 (range 38-65yr) entered the definitive study, seven women and five men. They each signed forms of consent after explanation of the nature of the experiment.
Key words: r.-tryptophan, sleep latency, diet. 1025
PH TL PL TH
TH PL TL PH
PL TH PH TL
TL PH TH PL
It had first been ascertained what customary foods each individual subject liked to eat and a list was drawn up for each subject of foods that they were to have on the evening of the low carbohydrate meal and foods that they could have on the evening of the high carbohydrate meal. On each experimental day each subject kept a diary of diet, which confirmed that they had indeed kept to the diet. It was thought important not to impose a rigid diet on subjects but to allow them to eat foods to which they were accustomed. Subjects came to the laboratory at about 21 :OOhr, usually by taxi, and had not drunk any alcohol or taken any aspirin during the preceding few days, nor any CNS drugs during the preceding few months. Silver disc electrodes were attached to the scalp for the recording of EEG, EOG and submental EMC. Lights-out varied, de~nding upon the wishes of the individual subjects. but lay between 22:OO and 22: 30 hr. In order to ensure that the double-biind nature of the study (as far as tryptophan was concerned) was maintained, the records were all coded by a colleague and scored “blind” by KA and IO working together and each in agreement on each measure of latency. Three latency criteria were employed (a) the time between lights-out and the first onset of stage 2 sleep (b) the latency to that transition from wakefulness into stage 1 that was followed by stage 2 sleep. without any return to wakefulness (c) latency to first stage
KIRSTIW AVAV and I. OSWALD Table
1. Lack of effect of tryptophan
or diet on latency
to sleep onbet
(bi
First stage 1
(a)
~.-
First stage 2 sleep
rollowed by stage 2 sleep
50.6
43.7 (14.9-93.0) 41.5
-._
Mean tryptophan
(21.099.51 Mean placebo
47.x (2W ‘14.4) 46.9 (16.5 X1.7) 51.5 (‘I.%103.5)
Mean high carbohydrate Mean low carbohydrate
Table 2, Lack OTeffect of tryptophan
Treatment
Diet
Tryptophan
High carbohydrate Low carbohydrate
Placebo
High carbohydrate
Low carbohydrate
1 (drowsiness). data collated.
Finally the code was broken
(cl First stage
{ 13.4xx.01 40.3 (X.7 X0.0) 44.8 (13.9.98.7)
plus high carbohydrate
17.6 (3.9 44.2) 1x.4
(3.2 61.3) 17.7
(bi First stage 1 followed by stage 2 sleep
43.2 (l&7-9Y.31 57.9 (~l.~-l6Y.(t) 50.5 (18.0 127.7) 45.0 ([email protected])
36.4 (3.7 93.0) 50.9 (14.7 163.0) 44.3 (10.7-122.0) 38.6 (13.0 113.3)
RESULTS
The results first confirmed the eRicacy of the initial selection procedures in selecting a population of subjects who had genuine di~~ulty in failing asleep. since the overall mean among the subjects on the experimental nights was 49 min to the first stage 2 sleep. Table 1 gives the mean latencies to the onset of sleep for the 12 subjects under each of the four conditions. The mean latency to stage 2 was 50.6 min after tryptophan and 47.X min after placebo. The mean after a high carbohydrate meal was 46.9 min and after a low carbohydrate meal 51.5 min and there is no suggestion of any difference in the effects of placebo, tryptophan, high carbohydrate. or low carbohydrate meal on any of the measures of sleep latency. Table 2 shows the mean latencies under the four combinations of conditions and there are no noteworthy differences among the conditions on the different measures of sleep latency.
The carbohydrate content in the evening meal had been varied systematically because diet can alter the
(4.7-41.3)
1x.3 (5.0-64.2)
meal on latency
(a) Fxst stage 2 sleep
and the
1
to sleep onset
(c) First stage
1
15.7 (2.3 41.3) 19.5 (3.G47.0) 19.6 (5.0.-48.3) 17.1 (3.3-81.3)
uptake of tryptophan into the brain (Wurtman and Fernstrom, 1974). A high carbohydrate meal should increase brain tryptophan in humans through the action of insulin. whereas a high protein meal, though it might contain more tryptophan, should raise the blood but not the brain level of tryptophan. However, even with this addition to the design, there was no suggestion that I g of tryptophan 20 min before lightsout made any difference to the time taken to fall asleep by subjects whose natural delays were of the same order as those of patients who complain about difficulty in falling asleep. The present study therefore lends no support to the notion that tryptophan. in a dose of 1 g at bedtime, might be of use under clinical conditions. lt may be remarked that there is generally a very wide variation from night to night in the sleep latency of normal people as well as those who have difhculty in falling asleep, and this alone makes it difbcuit to get a statistically significant difference in sleep latency when comparing placebo with established hypnotic drugs. In the present study, however, inspection of the data reveals that there is no reason to attribute the lack of difference to this factor alone: it is simply a Fact that the latencies were much the same under all ex~rimenta1 conditions. .~~~itnowieL~~u~ne,,t-Wewould Townsend able help.
like and Berk Pharmaceuticals
to thank Dr Helen Ltd for their invalu-
Tryptophan
fAils to alter sleep latenq
REFERENCES
Hartmann. E. and Ellon. ing in a strange place’. phurmcrwlog~ 53: 131-l Hartmann, E.. Cravens. effects of L-tryptophane.
R. (1977). The insomnia of ‘sleepEffects of L-tryptophane. P.~~c/~P 33. J. and List, S. (1974). Hypnotic Arc/u qw. P.s~chiut. 31: 394397.
1027
Rechtschaffen. A. and Kales. A. (1968). A Manua/ of Srwltlurdi~rti Trrminoloy~. Techniques unrl Scoring Sysrrm .jirr Slrrp Stuye.s of Humcrn S~hjrcrs. Washington. D.C.: U.S. Government Printing Office, NIH Publication. No. 204. Wurtman. R. J. and Fernstrom, J. D. (1974). Effects of the diet on brain neurotransmitters. Nurr. Rcr. 71: 193-X0.
CRAM THE
OF L-TRYPTOP~AN TIME
TAKEN
TO
FAILS TO ALTER FALL
ASLEEP
KIRSTNE ADAM and I. OSWALD liniversity Dept Psychiatry, Morningside Park, Edinburgh EHIO SHF, U.K.
It has been claimed by Hartmann and his colleagues that 1 g of t-tryptophan, taken 20min prior to retiring will shorten the deiay to the onset of sleep. In the first publication in which this was claimed (Hartmann, Cravens and List, 1974), 10 normal subjects aged 21--35 yr were used and seven different doses, between 1 and 15 g tryptophan or placebo alone, were used on different nights. Full details of the design are not given but it is obvious that the order of presentation could not have been balanced. In the evaluation, multiple t-tests were used; this is an invalid procedure as sleep latencies do not fall into a normal distribution. In defining the onset of sleep, stage 1 sleep was used, contrary to usual international practice, whereby sleep onset is taken as the first stage 2 sleep, with EECi sleep spindles (Rechtscha~en and Kales, 19613).Stage 1 is hard to define and when people are falling asleep stage 1 (drowsiness) comes and goes for a few seconds at a time, many times over. In a subsequent paper (Hartmann and Elion, 19773, 42 normal college students were used. They were not used as their own controls and 14 who took placebo at bedtime were compared with 14 who took L-tryptophan 1 g. A significant difference between tryptophan 1 g and placebo was claimed but once again there can be criticisms as there is no mention of prior matching of these groups for the length of time they usually took to fall asleep and there is no information about the time when they were put to bed in relation to their normal time of going to bed.
There were four experimental nights. On all these nights the subjects took two pills 20 min before lightsout. On two nights the pills were inert and on two nights contained a total of 1 g of L-tryptophan. In addition, subjects varied their evening diets according to a planned design, such that when they had their evening meal, at the customary time (always before 2O:OOhr), they ate a low carbohydrate meal on two of the experimental nights and a high carbohydrate meal on the other two nights. The design was such that there was balance among all four conditions, so that four subjects would have, where P = placebo, H = high T = tryptophan, carbohydrate and L = low carbohydrate:
,METHODS
The agreement of the Royal Edinburgh Hospital Ethics Committee was obtained. Initially subjects aged 35-65 yr were enrolled if they reported taking a long time to fall asleep and were given four preliminary nights in the sleep laboratory. On all nights full laboratory procedures were used but recordings were only made on the third and fourth nights. Subjects were accepted into the study only if the latency to stage 2 sleep on the third and fourth nights averaged over 25 min. Twelve subjects of mean age 54 (range 38-65yr) entered the definitive study, seven women and five men. They each signed forms of consent after explanation of the nature of the experiment.
Key words: r.-tryptophan, sleep latency, diet. 1025
PH TL PL TH
TH PL TL PH
PL TH PH TL
TL PH TH PL
It had first been ascertained what customary foods each individual subject liked to eat and a list was drawn up for each subject of foods that they were to have on the evening of the low carbohydrate meal and foods that they could have on the evening of the high carbohydrate meal. On each experimental day each subject kept a diary of diet, which confirmed that they had indeed kept to the diet. It was thought important not to impose a rigid diet on subjects but to allow them to eat foods to which they were accustomed. Subjects came to the laboratory at about 21 :OOhr, usually by taxi, and had not drunk any alcohol or taken any aspirin during the preceding few days, nor any CNS drugs during the preceding few months. Silver disc electrodes were attached to the scalp for the recording of EEG, EOG and submental EMC. Lights-out varied, de~nding upon the wishes of the individual subjects. but lay between 22:OO and 22: 30 hr. In order to ensure that the double-biind nature of the study (as far as tryptophan was concerned) was maintained, the records were all coded by a colleague and scored “blind” by KA and IO working together and each in agreement on each measure of latency. Three latency criteria were employed (a) the time between lights-out and the first onset of stage 2 sleep (b) the latency to that transition from wakefulness into stage 1 that was followed by stage 2 sleep. without any return to wakefulness (c) latency to first stage
KIRSTIW AVAV and I. OSWALD Table
1. Lack of effect of tryptophan
or diet on latency
to sleep onbet
(bi
First stage 1
(a)
~.-
First stage 2 sleep
rollowed by stage 2 sleep
50.6
43.7 (14.9-93.0) 41.5
-._
Mean tryptophan
(21.099.51 Mean placebo
47.x (2W ‘14.4) 46.9 (16.5 X1.7) 51.5 (‘I.%103.5)
Mean high carbohydrate Mean low carbohydrate
Table 2, Lack OTeffect of tryptophan
Treatment
Diet
Tryptophan
High carbohydrate Low carbohydrate
Placebo
High carbohydrate
Low carbohydrate
1 (drowsiness). data collated.
Finally the code was broken
(cl First stage
{ 13.4xx.01 40.3 (X.7 X0.0) 44.8 (13.9.98.7)
plus high carbohydrate
17.6 (3.9 44.2) 1x.4
(3.2 61.3) 17.7
(bi First stage 1 followed by stage 2 sleep
43.2 (l&7-9Y.31 57.9 (~l.~-l6Y.(t) 50.5 (18.0 127.7) 45.0 ([email protected])
36.4 (3.7 93.0) 50.9 (14.7 163.0) 44.3 (10.7-122.0) 38.6 (13.0 113.3)
RESULTS
The results first confirmed the eRicacy of the initial selection procedures in selecting a population of subjects who had genuine di~~ulty in failing asleep. since the overall mean among the subjects on the experimental nights was 49 min to the first stage 2 sleep. Table 1 gives the mean latencies to the onset of sleep for the 12 subjects under each of the four conditions. The mean latency to stage 2 was 50.6 min after tryptophan and 47.X min after placebo. The mean after a high carbohydrate meal was 46.9 min and after a low carbohydrate meal 51.5 min and there is no suggestion of any difference in the effects of placebo, tryptophan, high carbohydrate. or low carbohydrate meal on any of the measures of sleep latency. Table 2 shows the mean latencies under the four combinations of conditions and there are no noteworthy differences among the conditions on the different measures of sleep latency.
The carbohydrate content in the evening meal had been varied systematically because diet can alter the
(4.7-41.3)
1x.3 (5.0-64.2)
meal on latency
(a) Fxst stage 2 sleep
and the
1
to sleep onset
(c) First stage
1
15.7 (2.3 41.3) 19.5 (3.G47.0) 19.6 (5.0.-48.3) 17.1 (3.3-81.3)
uptake of tryptophan into the brain (Wurtman and Fernstrom, 1974). A high carbohydrate meal should increase brain tryptophan in humans through the action of insulin. whereas a high protein meal, though it might contain more tryptophan, should raise the blood but not the brain level of tryptophan. However, even with this addition to the design, there was no suggestion that I g of tryptophan 20 min before lightsout made any difference to the time taken to fall asleep by subjects whose natural delays were of the same order as those of patients who complain about difficulty in falling asleep. The present study therefore lends no support to the notion that tryptophan. in a dose of 1 g at bedtime, might be of use under clinical conditions. lt may be remarked that there is generally a very wide variation from night to night in the sleep latency of normal people as well as those who have difhculty in falling asleep, and this alone makes it difbcuit to get a statistically significant difference in sleep latency when comparing placebo with established hypnotic drugs. In the present study, however, inspection of the data reveals that there is no reason to attribute the lack of difference to this factor alone: it is simply a Fact that the latencies were much the same under all ex~rimenta1 conditions. .~~~itnowieL~~u~ne,,t-Wewould Townsend able help.
like and Berk Pharmaceuticals
to thank Dr Helen Ltd for their invalu-
Tryptophan
fAils to alter sleep latenq
REFERENCES
Hartmann. E. and Ellon. ing in a strange place’. phurmcrwlog~ 53: 131-l Hartmann, E.. Cravens. effects of L-tryptophane.
R. (1977). The insomnia of ‘sleepEffects of L-tryptophane. P.~~c/~P 33. J. and List, S. (1974). Hypnotic Arc/u qw. P.s~chiut. 31: 394397.
1027
Rechtschaffen. A. and Kales. A. (1968). A Manua/ of Srwltlurdi~rti Trrminoloy~. Techniques unrl Scoring Sysrrm .jirr Slrrp Stuye.s of Humcrn S~hjrcrs. Washington. D.C.: U.S. Government Printing Office, NIH Publication. No. 204. Wurtman. R. J. and Fernstrom, J. D. (1974). Effects of the diet on brain neurotransmitters. Nurr. Rcr. 71: 193-X0.