Tolerance

Speculation A

and

Dependence to

Serotonin

Richard J. Wyatt, MD; Jonathan Kaplan, MD; Thomas Vaughan, MD, Washington, DC
In a therapeutic trial, rapid increases and abrupt discontinuation of the serotonin precursor 5-hydroxytryptophan (5 HTP) produced The peripheral decarboxylase inhibitor is thought not to enter the brain and because it prevents the conversion of 5HTP to serotonin outside the central nervous system (CNS), makes more 5HTP available for conversion to serotonin within the brain parenchyma. Placebo and active drugs were given in equal numbers in identical capsules. The dosage (150 mg/24 hr) of the peripheral decarboxylase inhibitor remained constant throughout the 5HTP (up to 10 gm/24 hr) and withdrawal phases of the study. Known and potential risks of 5HTP were described to the patients and their families prior to admission to the research ward. Written consent was obtained with the proviso that the patients could withdraw from the study at any time.

striking behavioral effects in a group of phenothiazine-resistant chronic schizophrenic patients. These effects were greatly diminished by gradual changes in 5HTP dosages.
It is

administration in these patients and perhaps to serotonin itself. It is further speculated that rapid changes, even from normal serotonin concentration, might be responsible for many of the behavioral effects seen when the metabolism of serotonin is altered.

speculated that tolerance and dependence developed to 5HTP

\everal

observations

Xytryptophan (5HTP) in chronic schizophrenic patients Sgest that under some circumstances 5HTP may be caole of producing both tolerance and dependence. The rPose of the therapeutic trial, described in detail elsehere,' - was to study the effects of 5HTP administration Oh i Phenothiazine refractory chronic schizophrenic patiet)ts. The results of that therapeutic trial are reviewed ere briefly. To date 11 patients have been studied. Comj feu to placebo, seven improved, two became worse, and Wo no change could be determined; the 5HTP was not ,. spared to phenothiazine treatment and none of the pats at their best would have been able to leave the hosal for long periods of time. When the disturbing effects led below were recognized, the experimental protocol s altered to prevent them.
. .

trial of the immediate serotonin precursor, -5-hy-

made during

therapeutic

Results

Method

therapeutic trial, 11 phenothiazine-resistant chronic schizowere placed on placebo for one month, -5HTP 5|U1 il, f le periiiheral decarboxylase inhibitor, carbidopa (MK-486), three months, and then placebo for a second one-month period.
etlic patients
From
for publication May 14, 1973. Accepted the Laboratory of Clinical Psychopharmacology, IRP National In-

na

Increases of 5HTP greater than 200 mg/24 hr generally led to nausea, vomiting, diarrhea, diaphoresis, mild diastolic hypotension, and a motoric and psychic hyperkinetic syndrome. The increased motor activity took the form of restlessness, hand wringing, pacing, and an inability to sit quietly in a chair. The increased psychic activity took the form of transient increases in hallucinations, delusions, marked confusion, looseness of associations, and flight of ideas. In all cases, these effects could be partly or entirely reduced by scheduling gradual increases in 5HTP (50 to 100 mg/24 hr). Except for two patients who became clinically worse with 5HTP, tolerance was developed for each of the above side effects. In five patients, the effects persisted until the dosage exceeded 2,500 to 3,000 mg/24 hr. Once these higher dosages were reached, symptoms disappeared. Substitution of placebo for MK-486 greatly lessened these effects. In six patients whose 5HTP dosage was suddenly discontinued, varying degrees of coryza, diaphoresis, tremulousness, and hallucinations were seen. In the most severe cases confusion, delirium, and convulsions also occurred.

stitute of Mental Health, Saint Reprint requests to the LaboraIPof CsytRchloipnarmPcoyalg, National Institute of Mental WHESai loiaezspbhleintahglts,ton, DC 20032

Elizabeths

Hospital, Washington, DC.

(Dr. Wyatt).

Report of Cases Case l.-A 30-year-old male chronic paranoid schizophrenic patient was receiving phenothiazines and butyrophenones. He was suspicious and delusional with a few lucid periods. He paced the

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halls, with eyes darting from side to side. He occasionally became hostile enough to hit the staff and other patients. On placebo, he remained virtually unchanged. When he was started on 5HTP, he became continuously delusional, more agitated, and yelled an unintelligible word salad. As the 5HTP dosage was raised, he became more hyperactive and incapable of sitting still even long enough to eat. He perspired through three or four hospital suits in an eight-hour shift. Because of his deteriorating condition, the 5HTP was abruptly terminated from a 3,000 mg/24 hr dosage. Within eight hours, his symptoms became even more pronounced and he was extremely concerned that he be saved from imaginary attackers. Eighty-four hours after his last drug dosage, he suffered a grand mal seizure. Case 2.-A 25-year-old male, chronic undifferentiated schizophrenic patient was receiving haloperidol which made him somewhat overcontrolled, but very compliant. He handled "everything with intellectualization, avoided any comments about his personal feelings, and had infrequent outbursts of anger. On placebo, he was more talkative and affiliative, but also more delusional. After he had been on the maximal 5HTP dosage of 6,000 mg/24 hr for one month, his delusions were less prominent. Placebo capsules were abruptly substituted for 5HTP. Nine hours after his last 5HTP capsule, his demeanor changed markedly. He became tremulous, had coryza, and perspired profusely. He was loud, overtly hostile, and frankly hallucinatory. As the hours passed, he became more and more hyperactive and appeared to be increasingly frightened by his hallucinations. Small noises sent him into an angry panic and he seemed inordinately vigilant toward his surroundings. Seventeen hours after his last 5HTP capsule, he developed a grand mal seizure. This responded to anticonvulsive therPatient 1 had had an isolated grand mal seizure at age 5, but no other convulsive history. Patient 2 also had an isolated seizure as an infant and again at age 15. Since seizures occurred in only two of six patients whose dosage was suddenly terminated, it may have been that they had a lowered seizure threshold. In the four other patients, striking changes took place following abrupt withdrawal of the drug including a vast increase in hallucinatory behavior with the hallucinations being more frightening and lifethreatening than usual. During these panic states, the patients' pupils were dilated, they sweated profusely, they paced constantly, and were incapable of sleeping. These symptoms subsided gradually over a four- to six-day period on placebo. When the 5HTP dosage was gradually decreased over a week or more, this syndrome was greatly reduced, although there was frequently a gradual deterioration of behavior. In one patient receiving 9,000 mg 5HTP per 24 hours, the syndrome partially developed (following an abrupt discontinuation of the drug when he eloped) after 22 hours had passed since the last capsule. On his return to the hospital, he was immediately restarted on 5HTP and given intramuscular diazepam. The agitation and bizarreness disappeared.
apy

ical abnormality.' The chronic schizophrenic patients in this study deve'' oped what appeared to be both CNS tolerance (the lessd1' ing of brain effects produced by repeated dosages of th1 drug) and dependence (the appearance of a withdraw* syndrome following the discontinuance of the drug) t0 5HTP. It should immediately be noted that the extraoro'' narily large dosage of 5HTP used in this research, the n*' ture of the subjects, and the unexpected and therefore t" unsystematic manner in which the observations wefe made prevent us from making any generalizations. The>

(diazepam).

The behavioral changes occurring with abrupt alter3' tion in 5HTP dosage could be due to 5HTP itself, serotonin, or one of its metabolites. There is little evidenc that 5HTP is active in the CNS except after conversion t serotonin. Since the hyperactivity occurring with large i"' creases in the dosage of 5HTP in the schizophrenic patie" has also been reported in rodents with' and without a m9" noamine oxidase inhibitor'' it is suggestive that seroton1 is producing the hyperactivity rather than one of its n^ tabolites. In man there is evidence that orally admin,s' tered 5HTP is converted in the brain to serotonin. In u laboratory (unpublished data) as well as those of Chasec a!' and Brodie et al" evidence of increased of the principal metabolite of serotonin (5-hydroxyindo acetic acid) in the spinal fluid of patients who receWe 5HTP has been found. This presumably indicates that serotonin is also elevated under these conditions. Animal studies indicate that the serotonin which formed from 5HTP is largely (but not necessarily co"1 pletely) formed in neurons other than those which n0 mally contain serotonin.7'" This is probably due to t*1 ubiquitous nature of the enzyme that converts 5HTP serotonin (5HTP-dopa decarboxylase). If serotonin is ^ substance which produces the behavioral changes, it i""' be acting in an unphysiological manner, by being in neurons that contain it as a "false or substitute tra" j mitter." The apparent serotonin-induced behavi"1" changes would then be due to alterations in an unidc tified monoaminergic system.

do, however, provoke

some

speculations.

concentration

pres^

Is There Evidence That Endogenous Serotonin Plays a R In the Development of Tolerance and Dependence?

Comment

The

severe

deleterious effects observed when chronic

schizophrenic patients' 5HTP dosage was rapidly altered could be greatly decreased when gradual drug changes were made. While there is no evidence that abrupt alterations in 5HTP dosage will cause similar phenomena in nonschizophrenic patients it is important for researchers working with 5HTP to recognize this symptomatology if it occurs. It is possible, for example, that a recent report of marked worsening in patients with Parkinson syndrome given -5HTP and MK-496 was reflecting the rate the 5HTP dosage was increased rather than a basic patholog-

it.

unlike 5HTP, is converted to serotonin primarily n that normally contain serotonin. If tolerance does j velop to tryptophan loading it would suggest that the fects are due to serotonin in serotonergic cells. .f There is some evidence that at least one organ ^ than the brain can develop tolerance to increased &e tonin concentration. Rat colon normally responds to se tonin by contracting. Rat colon preparations that are prolonged contact with serotonin become insensitive
rons
.

together with a monoamine oxidase in*111 peripheral decarboxylase inhibitor"" develop hyperactive motoric syndrome similar to that seen in ,s schizophrenic patients. It is not known if these ani"1 develop tolerance to tryptophan or 5HTP but tryptop9
phan
tor4
or

t(r Rats, mice, and rabbits given large dosages of tryP..

5HTP

or a

"L

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Cats administered large dosages of parachlorophenylalKwe (PCPA), a drug which blocks the first and rate limit"6 enzymatic step in serotonin synthesis, and con-

^lUently ecome

serotonin concentrations and "appear to halluciAfter about a week of continued PCPA adminisration and while the brain serotonin remains low the ^s' behavior returns to normal. Rats who have habitto a novel stimulus lose their habituation after "PA administration but with time are able to rhabitThese data suggest that animals can adapt to rapid '^rations from normal brain serotonin concentrations. "te chronic schizophrenic patients abruptly withdrawn rm high 5HTP dosages also seem to adapt to an abrupt Crease (from an abnormally high serotonin concentral0ri). These results also suggest that the rate of change in eftonin concentration may be more important in deterging behavioral change than the absolute serotonin

decreases

brain

nate." Jted
ue.12

hyperactive, insomniac,

clcentration. * highly controversial hypothesis,1'" 0

,

relates serotonin

piate tolerance and dependence. Data have been gen-

erated that opiates increase the turnover of mouse brain serotonin. Increasing brain serotonin concentrations in the schizophrenic patients produced tolerance and dependence in a similar (delirium and seizures, however, are more commonly associated with alcohol and barbiturates) fashion to that seen with opiates in man. In the schizophrenic patient, there was, however, no evidence of the euphoric effects associated with the opiates. Less speculatively it is commonly observed that many drugs affecting the CNS produce a mild to moderate withdrawal syndrome on discontinuation.'81" Since many of these same drugs are known to alter serotonin metabolism, it is possible that at least part of these withdrawal effects are due to alteration in serotonin. These findings and speculations regarding the development in man of tolerance and dependence to a natural substance (5HTP and serotonin are found endogenously) may well be unique to the situation described. It may be, however, that the findings are representative of a more general relationship between the CNS and serotonin (and perhaps other biogenic amines) and behavior.

References

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1.
2.

Wyatt RJ, et al: Behavioral changes of chronic schizophrenic patients given l-5-hydroxytryptophan. Science 177:1124-1126, 1972. Chase TN, Ng LKY, Watanabe AM: Parkinson's disease: 3. Modification by 5-hydroxytryptophan. Neurology 22:479-484, 1972. Studies in vivo on the relationship be4. Grahame-Smith DG: brain 5-HT synthesis and hyperactivity brain tryptophan, tween treated with a monoamine oxidase inhibitor and L-tryptoin pJ han. Neurochem 18:1053-1066, 1971. 5. Modigh K: Central and peripheral effects of 5-hydroxytryptophan on motor activity in mice. Psychopharmacologia
rats

6.
tonin

23:48-54, 1972. R, Siever L: Clinical studies of 5-hyBrodie HK, inSack depression, in Barchas J, Usdin E (eds): Serodroxytryptophan 549\x=req-\559. Academic Press and Behavior. New
York,
Inc, 1973, pp

Moir ABT, Eccleston D: The effects of precursor loading in 7. metabolism of 5-hydroxyindoles. J Neurochem thecerebral
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8.
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15:1093-1108,1968.

11. Dement W, et al: Some parallel findings in schizophrenic patients and serotonin-depleted cats, in Siva Sankar DV (ed): Schizophrenia: Current Concepts and Research. New York, PJD Publications Ltd, 1969, p 775. 12. Stok JM, Barkas JD, Conner RL: Relationship between brain serotonin and habituation to an auditory startle stimulus in the rat, in the Proceedings of the 78th Annual Convention of the American Psychological Association, Washington, DC, the association, 1970, pp 827-828. 13. Cheney DL, Goldstein A: The effect of p-chlorophenylalanine on opiate-induced running, analgesia, tolerance, and physical dependence in mice. J Pharmacol Exp Ther 177:309-315, 1971. 14. Marshall I, Grahame-Smith DG: Unchanged rate of brain serotonin synthesis during chronic morphine treatment and failure of parachlorophenylalanine to attentuate withdrawal syndrome in mice. Nature 228:1206-1208, 1970. 15. Way EL, Loh HH, Shen FH: Simultaneous quantitative assessment of morphine tolerance and physical dependence. J Pharmacol Exp Ther 167:1-8, 1969. 16. Shen FH, Loh HH, Way EL: Brain serotonin turnover in morphine tolerant and dependent mice. J Pharmacol Exp Ther

of

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5-hydroxytryptophan

in rabbits

by dl-\g=a\-hydrazino-\g=a\-methyl

amines: Effect of methysergide and 5-HT desensitization. Eur J Pharmacol 17:319-324, 1972.

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17.

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Way

EL: Role of serotonin in

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