Tolerance and Dependence to SerotoninASpeculation

RichardJ. Wyatt, MD; Jonathan Kaplan, MD; Thomas Vaughan, MD, Washington, DC

In a therapeutic trial, rapid increases and abrupt discontinuation ofthe serotonin precursor 5-hydroxytryptophan (5 HTP) producedstriking behavioral effects in a group of phenothiazine-resistant

chronic schizophrenic patients. These effects were greatly dimin-ished by gradual changes in 5HTP dosages.It is speculated that tolerance and dependence developed to 5HTPadministration in these patients and perhaps to serotonin itself. It is

further speculated that rapid changes, even from normal serotoninconcentration, might be responsible for many of the behavioral ef-

fects seen when the metabolism of serotonin is altered.

\everal observations made during a therapeutictrial of the immediate serotonin precursor, ¿-5-hy-

°Xytryptophan (5HTP) in chronic schizophrenic patientsSgest that under some circumstances 5HTP may be ca-ole of producing both tolerance and dependence. TherPose of the therapeutic trial, described in detail else-

here,' - was to study the effects of 5HTP administrationOh i

. Phenothiazine refractory chronic schizophrenic pa-et)ts. The results of that therapeutic trial are reviewedere briefly. To date 11 patients have been studied. Com-

j ïeu to placebo, seven improved, two became worse, andf Wo no change could be determined; the 5HTP was not

,. spared to phenothiazine treatment and none of the pa-. °ts at their best would have been able to leave the hos-

al for long periods of time. When the disturbing effectsled below were recognized, the experimental protocols altered to prevent them.

ti

Methodn a therapeutic trial, 11 phenothiazine-resistant chronic schizo-etlic patients were placed on placebo for one month, Í-5HTP5|U1 il,

f «le periiiheral decarboxylase inhibitor, carbidopa (MK-486),three months, and then placebo for a second one-month period.

The peripheral decarboxylase inhibitor is thought not to enter thebrain and because it prevents the conversion of 5HTP to serotoninoutside the central nervous system (CNS), makes more 5HTPavailable for conversion to serotonin within the brain paren-chyma. Placebo and active drugs were given in equal numbers inidentical capsules. The dosage (150 mg/24 hr) of the peripheral de-carboxylase inhibitor remained constant throughout the 5HTP (upto 10 gm/24 hr) and withdrawal phases of the study. Known andpotential risks of 5HTP were described to the patients and theirfamilies prior to admission to the research ward. Written consentwas obtained with the proviso that the patients could withdrawfrom the study at any time.

Results

Increases of 5HTP greater than 200 mg/24 hr generallyled to nausea, vomiting, diarrhea, diaphoresis, mild dia-stolic hypotension, and a motoric and psychic hyperkineticsyndrome. The increased motor activity took the form ofrestlessness, hand wringing, pacing, and an inability to sitquietly in a chair. The increased psychic activity took theform of transient increases in hallucinations, delusions,marked confusion, looseness of associations, and flight ofideas. In all cases, these effects could be partly or entirelyreduced by scheduling gradual increases in 5HTP (50 to100 mg/24 hr). Except for two patients who became clini-cally worse with 5HTP, tolerance was developed for eachof the above side effects. In five patients, the effects per-sisted until the dosage exceeded 2,500 to 3,000 mg/24 hr.Once these higher dosages were reached, symptoms dis-appeared. Substitution of placebo for MK-486 greatly less-ened these effects.

In six patients whose 5HTP dosage was suddenly dis-continued, varying degrees of coryza, diaphoresis, tremu-lousness, and hallucinations were seen. In the most severecases confusion, delirium, and convulsions also occurred.

Report of Cases

Case l.-A 30-year-old male chronic paranoid schizophrenic pa-tient was receiving phenothiazines and butyrophenones. He was

suspicious and delusional with a few lucid periods. He paced the

Accepted for publication May 14, 1973.From the Laboratory of Clinical Psychopharmacology, IRP National In-

stitute of Mental Health, Saint Elizabeths Hospital, Washington, DC.Reprint requests to the LaboratoryofClinicalPsychopharmacology,IRPNational Institute of MentalHealth,SaintElizabethsHospital,Washing-ton, DC 20032 (Dr. Wyatt).

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halls, with eyes darting from side to side. He occasionally becamehostile enough to hit the staff and other patients. On placebo, heremained virtually unchanged. When he was started on 5HTP, hebecame continuously delusional, more agitated, and yelled an

unintelligible word salad. As the 5HTP dosage was raised, he be-came more hyperactive and incapable of sitting still even longenough to eat. He perspired through three or four hospital suits inan eight-hour shift. Because of his deteriorating condition, the5HTP was abruptly terminated from a 3,000 mg/24 hr dosage.Within eight hours, his symptoms became even more pronouncedand he was extremely concerned that he be saved from imaginaryattackers. Eighty-four hours after his last drug dosage, he suf-fered a grand mal seizure.

Case 2.-A 25-year-old male, chronic undifferentiated schizo-phrenic patient was receiving haloperidol which made him some-what overcontrolled, but very compliant. He handled "everythingwith intellectualization, avoided any comments about his personalfeelings, and had infrequent outbursts of anger. On placebo, hewas more talkative and affiliative, but also more delusional. Afterhe had been on the maximal 5HTP dosage of 6,000 mg/24 hr forone month, his delusions were less prominent. Placebo capsuleswere abruptly substituted for 5HTP. Nine hours after his last5HTP capsule, his demeanor changed markedly. He became trem-ulous, had coryza, and perspired profusely. He was loud, overtlyhostile, and frankly hallucinatory. As the hours passed, he becamemore and more hyperactive and appeared to be increasinglyfrightened by his hallucinations. Small noises sent him into an

angry panic and he seemed inordinately vigilant toward his sur-

roundings. Seventeen hours after his last 5HTP capsule, he devel-oped a grand mal seizure. This responded to anticonvulsive ther-apy (diazepam).

Patient 1 had had an isolated grand mal seizure at age 5, but noother convulsive history. Patient 2 also had an isolated seizure asan infant and again at age 15. Since seizures occurred in only twoof six patients whose dosage was suddenly terminated, it mayhave been that they had a lowered seizure threshold. In the fourother patients, striking changes took place following abrupt with-drawal of the drug including a vast increase in hallucinatory be-havior with the hallucinations being more frightening and life-threatening than usual. During these panic states, the patients'pupils were dilated, they sweated profusely, they paced con-stantly, and were incapable of sleeping. These symptoms subsidedgradually over a four- to six-day period on placebo. When the5HTP dosage was gradually decreased over a week or more, thissyndrome was greatly reduced, although there was frequently agradual deterioration of behavior.

In one patient receiving 9,000 mg 5HTP per 24 hours, the syn-drome partially developed (following an abrupt discontinuation ofthe drug when he eloped) after 22 hours had passed since the lastcapsule. On his return to the hospital, he was immediately re-started on 5HTP and given intramuscular diazepam. The agita-tion and bizarreness disappeared.

CommentThe severe deleterious effects observed when chronic

schizophrenic patients' 5HTP dosage was rapidly alteredcould be greatly decreased when gradual drug changeswere made. While there is no evidence that abrupt altera-tions in 5HTP dosage will cause similar phenomena innonschizophrenic patients it is important for researchersworking with 5HTP to recognize this symptomatology ifit occurs. It is possible, for example, that a recent report ofmarked worsening in patients with Parkinson syndromegiven ¿-5HTP and MK-496 was reflecting the rate the5HTP dosage was increased rather than a basic patholog-

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 th1drug) and dependence (the appearance of a withdraw*syndrome following the discontinuance of the drug) t05HTP. 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 wefemade prevent us from making any generalizations. The>do, however, provoke some speculations.

The behavioral changes occurring with abrupt alter3'tion in 5HTP dosage could be due to 5HTP itself, sero-tonin, or one of its metabolites. There is little evidencthat 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 seroton1is 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 °ulaboratory (unpublished data) as well as those of Chaseca!' and Brodie et al" evidence of increased concentrationof the principal metabolite of serotonin (5-hydroxyindoacetic acid) in the spinal fluid of patients who receWe5HTP has been found. This presumably indicates that se-rotonin is also elevated under these conditions.

Animal studies indicate that the serotonin whichformed from 5HTP is largely (but not necessarily co"1pletely) 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 5HTPserotonin (5HTP-dopa decarboxylase). If serotonin is ^substance which produces the behavioral changes, it i""'be acting in an unphysiological manner, by being pres^in neurons that contain it as a "false or substitute tra" jmitter." The apparent serotonin-induced behavi"1"changes would then be due to alterations in an unidctified monoaminergic system.Is There Evidence That Endogenous Serotonin Plays a R°

In the Development of Tolerance and Dependence?t(rRats, mice, and rabbits given large dosages of tryP..

phan or 5HTP together with a monoamine oxidase in*111¡tor4 or a peripheral decarboxylase inhibitor"" develophyperactive motoric syndrome similar to that seen in ,sschizophrenic patients. It is not known if these ani"1develop tolerance to tryptophan or 5HTP but tryptop»9unlike 5HTP, is converted to serotonin primarily ¡n "¡Lrons that normally contain serotonin. If tolerance does j

velop to tryptophan loading it would suggest that thefects 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 &etonin concentration. Rat colon normally responds to setonin by contracting. Rat colon preparations that areprolonged contact with serotonin become insensitiveit.»

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

^lUently decreases brain serotonin concentrationsecome hyperactive, insomniac, and "appear to halluci-

nate."» After about a week of continued PCPA adminis-ration and while the brain serotonin remains low the^s' behavior returns to normal. Rats who have habit-Jâted to a novel stimulus lose their habituation after"PA administration but with time are able to réhabit-ue.12 These data suggest that animals can adapt to rapid'^rations from normal brain serotonin concentrations."te chronic schizophrenic patients abruptly withdrawnr°m high 5HTP dosages also seem to adapt to an abruptCrease (from an abnormally high serotonin concentra-l0ri). These results also suggest that the rate of change inef°tonin concentration may be more important in deter-ging behavioral change than the absolute serotonin

c°lcentration.,

* highly controversial hypothesis,1'" relates serotonin0 °piate tolerance and dependence. Data have been gen-

erated that opiates increase the turnover of mouse brainserotonin. Increasing brain serotonin concentrations inthe schizophrenic patients produced tolerance and depen-dence in a similar (delirium and seizures, however, aremore commonly associated with alcohol and barbiturates)fashion to that seen with opiates in man. In the schizo-phrenic patient, there was, however, no evidence of theeuphoric effects associated with the opiates.

Less speculatively it is commonly observed that manydrugs affecting the CNS produce a mild to moderate with-drawal syndrome on discontinuation.'81" Since many ofthese same drugs are known to alter serotonin metabo-lism, it is possible that at least part of these withdrawaleffects are due to alteration in serotonin.

These findings and speculations regarding the develop-ment in man of tolerance and dependence to a naturalsubstance (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 (andperhaps other biogenic amines) and behavior.

References

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2. Wyatt RJ, et al: Behavioral changes of chronic schizophrenicpatients given l-5-hydroxytryptophan. Science 177:1124-1126, 1972.3. Chase TN, Ng LKY, Watanabe AM: Parkinson's disease:

Modification by 5-hydroxytryptophan. Neurology 22:479-484, 1972.4. Grahame-Smith DG: Studies in vivo on the relationship be-tween brain tryptophan, brain 5-HT synthesis and hyperactivityin rats treated with a monoamine oxidase inhibitor and L-trypto-phan.J Neurochem 18:1053-1066, 1971.5. Modigh K: Central and peripheral effects of 5-hy-droxytryptophan on motor activity in mice. Psychopharmacologia23:48-54, 1972.6.Brodie HK, Sack R, Siever L: Clinical studies of 5-hy-droxytryptophan in depression, in Barchas J, Usdin E (eds): Sero-tonin and Behavior. New York, Academic Press Inc, 1973, pp 549\x=req-\559.

7. Moir ABT, Eccleston D: The effects of precursor loading inthecerebral metabolism of 5-hydroxyindoles. J Neurochem

15:1093-1108,1968.8. Fuxe K, Butcher L, Engel J: dl-5HTP induced changes incentral monoamine neurons after decarboxylase inhibition. J

Pharm Pharmacol 23:420-424, 1971.9. Horita A, Hamilton AE: Potentiation of the central actionsof 5-hydroxytryptophan in rabbits by dl-\g=a\-hydrazino-\g=a\-methyldopa. J Pharm Pharmacol 22:389-391, 1970.10. Gagnon DJ: Contraction of rat colon by sympathomimeticamines: Effect of methysergide and 5-HT desensitization. Eur J

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11. Dement W, et al: Some parallel findings in schizophrenic pa-tients and serotonin-depleted cats, in Siva Sankar DV (ed): Schizo-phrenia: Current Concepts and Research. New York, PJD Publi-cations Ltd, 1969, p 775.

12. Stok JM, Barkas JD, Conner RL: Relationship betweenbrain serotonin and habituation to an auditory startle stimulus inthe rat, in the Proceedings of the 78th Annual Convention of theAmerican Psychological Association, Washington, DC, the associ-ation, 1970, pp 827-828.

13. Cheney DL, Goldstein A: The effect of p-chlorophenylalanineon opiate-induced running, analgesia, tolerance, and physical de-pendence in mice. J Pharmacol Exp Ther 177:309-315, 1971.

14. Marshall I, Grahame-Smith DG: Unchanged rate of brainserotonin synthesis during chronic morphine treatment and fail-ure of parachlorophenylalanine to attentuate withdrawal syn-drome in mice. Nature 228:1206-1208, 1970.

15. Way EL, Loh HH, Shen FH: Simultaneous quantitative as-sessment of morphine tolerance and physical dependence. JPharmacol Exp Ther 167:1-8, 1969.

16. Shen FH, Loh HH, Way EL: Brain serotonin turnover inmorphine tolerant and dependent mice. J Pharmacol Exp Ther175:427-434, 1970.

17. Way EL: Role of serotonin in morphine effects. Fed Proc31:113-129, 1972.

18. Wyatt RJ, et al: Longitudinal studies of the effect ofmonoamine oxidase inhibitors on sleep in man. Psychopharmaco-logia 15:236-274, 1969.

19. Wyatt RJ, et al: Total prolonged rapid eye movement sup-pression in anxious-depressed patients. Arch Gen Psychiatry24:145-155, 1971.

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