L-Tryptophan
White to almost white or slightly yellowish-white crystals or
crystalline or amorphous powder. Sparingly soluble in water;
slightly soluble in alcohol or soluble in hot alcohol; practical-
ly insoluble in ether: soluble in dilute hydrochloric acid. dis-
solves in dilute solutions of alkali hydroxides and mineral
acids. A 1% solution in water has a pH of 5.5 to 7.0. Protect
from light.
Adverse Effects
Tryptophan-containing products have been associated with
the eosinophilia-myalgia syndrome: for further details, see
below,
Other side-effects that have been reported include nausea,
headache, lightheadedness, and drowsiness.
An increased incidence of bladder tumours has been reported
in mice given L-tryptophan orally as well as in cholesterol pel-
lets embedded in the bladder lumen.
Eosinophilia-myalgia syndrome. In late 1989 the first no-
tification linking the eosinophilia-myalgia syndrome with the
use of tryptophan-containing products was made in the USA.
There followed a number of similar published case reports
from the USA, Europe, and Japan. Reviews of tryptophan-
associated eosinophilia-myalgia syndrome have noted that by
early 1990 over 1500 cases were known in the USA.
In early 1990 the Centers for Disease Control in the USA
summarised the features and known reports concerning the
syndrome. As the name implies the characteristic features
are an intense eosinophilia together with disabling fatigue and
muscle pain, although multisystem organ involvement and in-
flammatory disorders affecting the joints, skin, connective tis-
sue, lungs, heart, and liver have also been recorded.
Symptoms have generally developed over several weeks and
the syndrome has occurred in patients who had been receiving
tryptophan for many years previously with no untoward ef-
fect. In most patients slow and gradual improvement in the
degree of eosinophilia and other clinical manifestations has
followed the withdrawal of tryptophan, but in some patients
the disease has progressed despite withdrawal and there have
been fatalities. The inflammatory condition has necessitat-
ed the use of corticosteroids in some patients.
The eosinophilia-myalgia syndrome has been reported in pa-
tients taking both tryptophan-containing prescription prod-
ucts for depression and non-prescription dietary supplements
for a number of disorders including insomnia, the premen-
stnial syndrome, and stress: it does not appear to have oc-
curred in patients receiving amino-acid preparations
containing tryptophan as part of total parenteral nutrition reg-
imens. The recognition of this syndrome led to the withdraw-
al of tryptophan-containing products or severe restrictions
being imposed upon their use in many countries during 1990.
Various theories were proposed as to the reason for the asso-
ciation of tryptophan with this syndrome. Confusion existed
because the reports implicated a very wide range of products
from different manufacturers. More recent evidence, howev-
er, appears to have confirmed that contaminated tryptophan
has originated from a single manufacturer in Japan. Bulk
tryptophan is imported from Japan for manufacture into fin-
ished pharmaceutical dosage forms and it was noted in one of
these reports that a single product was often found to contain
two or more lots of powdered tryptophan that were blended
together during the production of tablets or capsules. Many
trace contaminants have been found in batches of tryptophan
associated with the syndrome. One contaminant has been
identified as 1.l'-ethylidenebis(tryptophan). Its inclusion in
bulk tryptophan powder appeared to coincide with alterations
in the manufacturing conditions that involved a change in the
strain of Bacillus amyloliquefaciens used in the fermentation
process and a reduction in the amount of charcoal used for
purification. Other investigations indicated the presence of
bacitracin-like peptides in batches of the contaminated tryp-
tophan. However, further work has provided only weak
support for an association between the syndrome and any one
particular contaminant and the causative agent remains to be
confirmed. Nonetheless, since the syndrome only appeared to
be associated with tryptophan from one manufacturer, tryp-
tophan preparations were reintroduced in the UK in 1994 for
restricted use under carefully monitored conditions.
Precautions
Tryptophan has been associated with eosinophilia-myalgia
syndrome and it is therefore recommended that patients re-
ceiving tryptophan should be closely monitored with particu-
lar care being paid to eosinophil counts, haematological
changes, and muscle symptomatology.
Patients taking tryptophan may experience drowsiness and if
affected they should not drive or operate machinery.
Abnormal metabolism of tryptophan may occur in patients
with pyridoxine deficiency and tryptophan is thus sometimes
given with pyridoxine supplements.
Interactions
Although tryptophan has been given as additional therapy lo
patients receiving MAOls in the belief that clinical efficacy
may be improved, it should be noted that the adverse effects
of either drug may also be potentiated. For further details,
see
Antidepressants under Interactions of Phenelzine.
Use of tryptophan with drugs that inhibit the reuptake of se-
rotonin may exacerbate the adverse effects of the latter and
precipitate the serotonin syndrome.
There have been occasional reports of sexual disinhibition in
patients taking tryptophan in conjunction with phenothi-
azines or benzodiazepines.
For a report of tryptophan reducing blood concentrations of
levodopa, see Nutritional Agents under Interactions for Lev-
odopap.
pharmacokinetics
Tryptophan is readily absorbed from the gastro-intestinal
tract. Tryptophan is extensively bound to plasma albumin. It
is metabolised in the liver by tryptophan pyrrolase. Metabo-
lites include hydroxy tryptophan, which is then converted to
serotonin, and kynurenine derivatives. Some tryptophan is
converted to nicotinic acid and nicotinamide. Pyridoxine and
ascorbic acid are cofactors in the decarboxylation and hy-
droxylation respectively of tryptophan; pyridoxine apparently
prevents the accumulation of the kynurenine metabolites,
Uses and Administration
Tryptophan is an amino acid which is an essential constituent
of the diet. Tryptophan and DL-tryptophan have been used as
dietary supplements.
Tryptophan is a precursor of serotonin. Because CNS deple-
tion of serotonin is considered to be involved in depression.
tryptophan has been used in its treatment. Although it has
been given alone, evidence of effectiveness is scant and
tryptophan has generally been used as adjunctive therapy in
depression. Pyridoxine and ascorbic acid are involved in the
metabolism of tryptophan to serotonin (see Pharmacokinet-
ics, above) and have sometimes been given concomitantly.
In many countries preparations containing tryptophan have
either been withdrawn from the market or their availability
severely restricted or limited because of its association
with the eosinophilia-myalgia syndrome. In the UK tryplophan
is restricted to use by hospital specialists only as an
adjunct to other antidepressant medication for patients
with severe and disabling depressive illness of more than 2
years' continuous duration who have failed to respond to an
adequate trial of standard antidepressant drug treatment.
In the treatment of depression the usual dose of tryptophan
is 1 g given three times daily, but some patients may require
up to 6 g daily in divided doses. Lower doses may be required
in the elderly especially those with renal or hepatic
impairment.
Depression. Tryptophan has only weak antidepressant
properties itself but it has been used in combination with oth
er antidepressants in the belief that it would potentiate
their effects. Although beneficial effects have been reported
in some patients given tryptophan with tricyclic
antidepressants or MAOls. alone or with lithium, evidence of
efficacy is mainly limited to case reports and small
controlled studies.
Since the publication of reports linking the use of tryptophan
with the eosinophilic-myalgia syndrome (see under Adverse
Effects, above) preparations containing tryptophan for de-
pression have either been withdrawn from the market or their
availability severely restricted and limited in many
countries.
In the UK tryptophan is restricted to use by hospital special-
ists only as an adjunct to other antidepressant medication for
patients with severe and disabling depressive illness of more
than 2 years continuous duration who have failed to respond
to an adequate trial of standard antidepressant during treat-
ment.
Dietary supplementation. The use of tryptophan as a di-
etary supplement has been reviewed. However, because of its
association with the eosinophilia-myalgia syndrome (see un-
der Adverse Effects, above), the addition of tryptophan to
food intended for human consumption is prohibited in some
countries.
Insomnia. Tryptophan, sometimes in the form of dietary
supplements, has enjoyed some popularity for the treatment
of insomnia. However, the point has been made that
in comparison with other hypnotics such as the benzodi-
azepines. the effects of tryptophan have been more difficult
to substantiate and enthusiasm for tryptophan has waned con-
siderably amongst sleep researchers. It should also be noted
that since the publication of reports linking the use of tryp-
tophan with the eosinophilia-myalgia syndrome (see under
Adverse Effects, above) Preparations indicated for insomnia
have been withdrawn from the market in many countries.