The Psychedelic Model of Schizophrenia: The Case of N,N-

Dimethyltryptamine

BY J. CHRISTIAN GILLIN, M.D., JONATHAN KAPLAN, M.D., RICHARD STILLMAN, M.D.,

AND RICHARD JED WYA11, M.D.

associates (3). One-third of the patients in these stud-

The authors review the research on N,N-
ies exhibited increased clinical symptoms without cvi-
dimethyltryptamine (DMT) as a possible
dence of organic brain dysfunction. These results sug-
‘ ‘schizotoxin. DMTproduces
‘ ‘ psychedelic effects
gest that methiomine increases the synthesis of am ab-
when administered to normal subjects, the means are
normally methylated substance, as yet unidentified,
present to synthesize it in man, it has occasionally
that was responsible for the observed clinical cx-
beenfound in man, and tolerance to its behavioral
acerbation.
effects is incomplete. However, DMT concentrations
Several substances have been proposed as cam-
have not been proven to differ significantly in
didates for the schizotoxim, including 3,4-dimethoxy-
schizophrenics and normal controls. Also, in vivo
phenylethylamime (pink spot), bufotenime, 5-methoxy-
synthesis ofDMThas not been convincingly
N,N-dimethyltryptamime , and N,N-dimethyltryp-
demonstrated, and the psychological changes it
tamime (DMT) (see figure 1). The first two substances
produces do not closely mimic the symptoms of
have not been shown to produce psychotic psychologi-
schizophrenia. The authors conclude that more data
cal changes when administered to normal imdivid-
are necessary before the validity ofthis theory can be
uals (4, 5); in the case of bufotemime, this may be be-
determined.
cause it does not cross the blood-brain barrier. Little is
known about 5-methoxy-DMT, although it has been re-
ported to produce psychedelic effects in normal mdi-
MANY THEORIES of schizophrenia arc based on the as- viduals (6), and urinary concentrations of 5-methoxy-
sumption that the illness is caused by a chemical sub- DMT have been noted to increase with clinical cx-
stance, a “schizotoxim,” that would mimic the clinical acenbation in schizophrenic patients (7). Figure 1
symptomatology of schizophrenia if it were isolated presents the postulated routes of synthesis of DMT
and administered to normal individuals. Am example of and 5-methoxy-DMT.
this research strategy is the tramsmcthylatiom hypothc- In this paper, we shall review current evidence on
sis, first proposed by Osmond and Smythies in the role of DMT as a causative agent in schizophrenia.
1952 (1). These researchers noted the similarity in Fortunately there are criteria (modeled after Koch’s
chemical structure of mescaline and morepimephnine, postulation) with which to evaluate a hypothesized
an observation that spurred the search for psychedelic schizotoxim. The following criteria were initially pro-
methylated metabolites of endogemous compounds in posed by Hollister (8) and have been slightly modified
schizophrenic patients that might account for halluci- here:
nations, delusions, and other clinical symptoms. 1 The substance
. must mimic important clinical as-
Interest in the tramsmethylation hypothesis was fur- pects of schizophrenia.
then stimulated by the work of Pollin and asso- 2. The substance must be found in man.
ciates (2), who reported in 1960 that methionine, a mat- 3. The precursor must be found in man.
ural methyl donor, administered in combination with a 4. The agent must be synthesized in man. (It remains
monoamine oxidase (MAO) inhibitor, exacerbated a logical possibility that it is of dietary origin.)
clinical symptoms in 3 of 9 schizophrenic subjects. 5. The agent must be differentially synthesized or
Since that time, methiomine has been administered to metabolized in schizophrenia.
schizophrenics in 10 studies reviewed by Cohen and 6. Tolerance to the agent should not develop. (This
assumes that schizophrenia is not caused by a sub-
stance that is present only briefly and sets irreversible
Presented at the 128th annual meeting of the American Psychiatric changes in progress.)
Association, Anaheim, Calif. , May 5-9, 1975. 7. Neunoleptic drugs must be capable of inhibiting
Drs. Gillin and Stillman are Research Psychiatrists, and Dr. Wyatt is the synthesis, increasing the metabolism, or amtagomiz-
Acting Chief, Laboratory of Clinical Psychopharmacology, National img the behavioral effects of the agent.
Institute of Mental Health, St. Ehizabeths Hospital, Washington,
D.C. 20032. Dr. Kaplan is Staff Psychiatrist, Menlo Park Veterans The body of our paper will consist of am examination
Administration Hospital, Menlo Park, Calif. of each of these criteria as they apply to DMT.

AmfPsvchiatrv 133:2, February /976 203

PSYCHEDELIC MODEL

FIGURE 1 TABLE 1
Postulated Routes of Synthesis of DMT and 5-Methoxy-DMT Subjective Effects of DMT Experienced by 15 Normal Volunteer Sub-
jects, in Percents
,CH,
CH.-Ch.--NH. -CH.--N
- NCH.
Subjective Effect Percent

H Visual hallucinations 100

Tryptamine N,N-dimethyltryptamine (DMT)
Hallucinations with eyes closed 100
Movement of surroundings 93
Difficulty talking 93
) (methyl donor)
Difficulty describing feelings 93
Relaxation 93
Difficulty concentrating 93
Colors seem brighter 87
Excitation 87
Thinking faster 87
Dry mouth 87
H
Tenseness 80
5-Hydroxytryptamine )serotonin) 5-methoxy-N, N-dimethyltryptamine )5-Methooy-DMT)
People look different 75
Depersonalization 60
Nausea 60
People have orange-red hue 53
DOES DMT PRODUCE SIGNIFICANT Hallucinating “real things” 27
Paranoia 20
SCHIZOPHRENIC-LIKE SYMPTOMS?
Auditory hallucinations 7

In 1956 Szara (9) found that the effects of DMT on

20 normal volunteer subjects were similar to those of
LSD and mescaline: visual illusions and hallucina-
tioms, distortions of spatial perception and body im- FIGURE 2
Mean DMT Concentrations in Whole BlOOd Following Injection of DMT
age, speech disturbances, and euphoria. A striking
in 15 Normal Volunteers
finding was that the effects of DMT began within 5 mm-
utes and ended within 1 hour after injection. Similar re-
suits have since been reported by Rosenberg and asso-
ciates (10) and Turner and Merlis (5).
In order to reexamine the psychological effects of
DMT and to correlate them with pharmacokinetic as-
pects, we administered .7 mg/kg of DMT intra-
muscularly to 15 male volunteers. Each subject was an
experienced user of LSD, mescaline, or other psyche- E

delic substances who expressed an intention to comtin-

C/)
uc using these agents in the future. All subjects were z
0
interviewed by two psychiatrists and were given a F-

complete medical history and examination prior to test- cc

F-
z
ing in order to ensure the absence of psychiatric and LU
C-)
physical impairment. z
0
C-)
Like previous investigators, we found that DMT F-
I
was a hallucinogen with rapid action and a short duna- 0

tion of effect. Psychological changes were evident 0

0
0
within 5 minutes of injection, peaked at about 10 to 15 -J
cc
minutes, and ended within 45 to 120 minutes. The ma-
jon psychological effects are shown in table 1 The sub- .

jects became so uncommunicative and withdrawn dun-

40 50 60 120
ing the drug experience that we were forced to inquire
TIME AFTER INJECTION (minutes)
about the subjective effects with simple “yes-no”
questions. Although all subjects reported visual dis-
tortions and illusions, these were color or spatial dis-
tortions rather than formed visual hallucinations. Only
I subject reported an auditory hallucination, a “buzz- mydriasis, tachycandia, and increased blood pressure.
ing bee’ ‘in his ear. We did not observe formal loosen- Blood levels of DMT (see figure 2), assayed by a gas
img of associations, although several subjects seemed chromatographic-mass spectrometric (GC-MS) isotop-
to have thought blocking. Two subjects had paranoid ic dilution technique, closely paralleled the psychologi-
symptoms that lasted less than am hour. cal and autonomic changes (1 1). Peak concentrations
These psychological changes were accompanied by of DMT, which averaged approximately 100 mg/mi,

204 Am J Psychiatry 133:2 , February 1976

 GILLIN, KAPLAN, STILLMAN, AND WYATT

were reached about 10 to 15 minutes after injection; earlier, less specific methods of analysis than with the
the concentration then fell rapidly to baseline, unde- later GC-MS techniques. Although DMT has occasion-
tectable levels within about 45 to 120 minutes after ad- ally been identified by GC-MS techniques in some sub-
ministration. jects, the concentration has been extremely low. Also,
the presence of DMT has not been reported more fre-
quemtly in patients with particular diagnoses or in psy-
IS DMT FOUND IN MAN? chiatric patients in general compared with normal con-
trols. The origin and significance ofthe identified DMT
Several investigators have reported the presence of is unknown. Although it might reflect endogenous syn-
DMT in blood and urine of psychiatric patients (see thesis, it could also result from diet, bacterial prod-
table 2). Positive reports were more common with the ucts, laboratory error, on other sources.

TABLE 2
Recent Research on DMT in the BlOOd and Urine of Schizophrenics

Number Number
Authors (in chronological order) Method* Sample Subjects Tested Positive

Helher and associates ( I 2) TLC, GLC Whole blood Acute unmedicated schizophrenics 5 5
Urine 2 2
Whole blood Chronic schizophrenics 9 0
Psychotic depressives I 0
Normal subjects 2 0
Rosengarten and associates ( 13) TLC Urine Schizophrenics 15 3
Narasimhachari and associates (14) TLC,GLC Serum Acute schizophrenics 22 13
Neurotics 5 I
Chronic schizophrenics 4 0
Normal subjects 10 2**
Mother of manic-depressive I I
Narasimhachari and associates (15) TLC,GLC Urine Chronic unmedicated schizophrenics 2h6*** 9
Normal subjects 56 0
Kanabusand associates (16) PC Urine Nonschizophrenics 16 1
Schizophrenics 26 4
Wyatt and associates (17) GC-MS Plasma Acute schizophrenics 10 0
Chronic schizophrenics 9 0
Psychotic depressives 10
Narasimhachari and associates Normal subjects 11

(18, 19) TLC, GLC, Urine Chronic schizophrenics 6 3

GC-MS Normal subjects 4 0
Axelsson and Nordgren (20) Gel C Plasma Acute and chronic schizophrenics 9 0
TEC Neurotics 4 0
Bidder and associates (21) GC-MS Whole blood Psychiatric patients 37 2
or plasma
Urine 39 7
Lipinski and associates (22) GC-MS Whole blood Chronic schizophrenics 6 0
or plasma Schizophreniform psychotics II 2
GC-MS Whole blood, Patients with hepatic coma 11 0
Normal subjects 11 0
Mandeh (23) Acute schizophrenics 35 6
plasma, serum Chronic schizophrenics 46 4
Nonschizophrenics 66 3
Normal subjects 84 4
Oon and associates (24) TLC,MS Urine Schizophrenics 42 20
Affective psychotics 30 4
Other psychotics 18 7
Neurotics 32 6
Normal subjects 20 1
Carpenter and associates (25) GC-MS Urine Acute schizophrenics 12 4
Normal controls 9 4

* TLC=thin layer chromatography, PC=paper chromatography, GLCgas-liquid chromatography, GC-MS=gas chromatography-mass spectrometry, Gel
C =gel chromatography.
** Doubtful.
*** Number of samples for 6 patients.

Am J Psychiatry 133:2, February 1976 205

PSYCHEDELIC MODEL

IS THE PRECURSOR OF DMT PRESENT IN MAN? Thus the failure of various investigators to find dc-
CAN DMT BE SYNTHESIZED IN MAN? vated concentrations of DMT in venous blood or urine
of schizophremics may be explained by the rapid me-
As figure 1 indicates, DMT is thought to be synthe- tabolism of this compound. If DMT is actually formed
sized from tryptarninc in a reaction catalyzed by am N- by lung NMT, then schizophrenia is a lung disease,
mcthyltnansferasc (N MT). Tryptaminc is reportedly and DMT may be transported directly from lung to
present in human lung and elsewhere (26). NMT activi- brain via the arterial system. Once DMT is exposed to
ty has been reported in human brain (27, 28) and liver, kidney, on muscle, it may be so rapidly metabo-
blood (29), but its highest activity and specificity is in lized that measurable concentrations cannot be detect-
human lung (30). Mandel and associates (30), using ed in venous blood.
GC-MS techniques, demonstrated in vitro conversion
ofN-rnethyltryptaminc to DMT in human lung. Wyatt
and associates (3 1) and Murphy and Wyatt (32) have DOES TOLERANCE TO DMT DEVELOP?
found that MAO activity in platelets is low in some
schizophrenics compared with control subjects, and
that this defect may be genetically determined. Low Since schizophrenia is a clinical syndrome that lasts
MAO activity may lead to elevated concentrations of for weeks to months in its acute forms and for years to
tryptamime, which would favor the synthesis of DMT. decades in its chronic forms, a biochemical theory
In vivo human synthesis of DMT has not been con- must be able to explain long-term symptoms. The is-
vincingly demonstrated to date. We studed 1 male sue of tolerance has been a major problem in the schiz-
chronic schizophrenic patient before and during admin- otoxim theory of schizophrenia. Tolerance to LSD,
istration of 45-60 mg/day of the MAO inhibitor phenel- mescaline, and psilocybin develops rapidly in man and
zinc. Although the patient was more hallucinatory and animals, for some if not all behavioral effects.
autistic on phenelzine than he had been during the pla- In our initial efforts, we found that tolerance did not
cebo period, DMT concentrations in venous blood did develop to unconditioned behavioral and EEG effects
not change from their very low placebo values (ap- of DMT in cats administered DMT twice daily for 15
proximately .07 ng/ml). We also studied another male days or every 2 hours for 24 hours (34). Also, lack of
schizophrenic patient before and during treatment behavioral tolerance has been reported in squirrel mom-
with 20 g/day of L-tryptophan, the biosynthetic pre- keys given DMT once daily for 38 days (35).
cursor of tryptamine. Again, there was no change in More recently, we studied the issue oftolerance in 4
blood DMT concentration. The patient’s clinical condi- normal male volunteers who received 0.7 mg/kg of
tion was not altered by L-tryptophan. DMT intramuscularly twice daily for 5 days. Repeated
administration did not consistently alter the peak
blood concentration of DMT; automomic changes in
pupil size, pulse, or heart rate; the number of psycho-
IS DMT SYNTHESIZED OR METABOLIZED logical items changed in a psychological scale; or the
DIFFERENTLY IN SCHIZOPHRENICS THAN IN frequency of errors in a test requiring the subject to
CONTROLS? cross out a specific number in a list of random mum-
bens. Three of the 4 subjects reported diminished sub-
Synthesis of DMT in man has yet to be conclusively jective “highs” on a scale of 0 to 10 after two to four
demonstrated, and little knowledge currently exists on injections of DMT, but their subjective responses were
the metabolism of DMT in schizophnemics compared variable from trial to trial and did not indicate a general
with normal control subjects. Szara (9) suggested two loss of responsiveness to DMT. Rather, these subjects
major routes of metabolism of DMT: 1) dcalkylation exhibited a variable or aperiodic partial tolerance to
and oxidative deaminatiom, leading to imdole-3-acctic DMT. This pattern is reminiscent of Koella and asso-
acid and 2) 6-hydroxylation followed either by glucuro- ciates’ report of a cyclic change in ambulation pro-
mide formation of 6-hydroxy-DMT or by dealkylatiom duced by LSD in goats (36). Further studies, including
and oxidative deamination leading to 6-hydroxyim- longer or more frequent trials with DMT, are neces-
doleacetic acid (33). To our knowledge, there have sany to fully evaluate this phenomenon.
been no studies comparing the concentrations of these This type of variable tolerance has also been re-
rnctabolites in schizophnenics and controls. ported recently by Kovacic and Domino (37), who
Our recent study of the effects of DMT on volunteer studied the suppressive effects of DMT on the operant
subjects (1 1) suggested that the drug is rapidly metabo- behaviorofappetitively conditioned rats who were giv-
lized. Assuming that DMT is distributed equally en DMT every 2 hours for periods of up to 21 days.
throughout the blood, we could account for only about B#{246}sz#{246}rm#{233}myi and Szara (38) reported that schizo-
2% of the administered dose at the time of the peak phremics are less sensitive to the effects of DMT than
blood concentration. Moreover, less than .01% of the controls. Ifschizophremics do show diminished respon-
administered dose was found in urine within 24 hours, siveness to DMT, this may result from increased me-
and most ofthat amount was excreted within the first 6 tabolism or variable tolerance resulting from long-term
hours. endogemous synthesis of DMT.

206 Am J Psychiatry 133:2, February 1976

 GILLIN, KAPLAN, STILLMAN, AND WYATT

DO NEUROLEPTICS INHIBIT THE SYNTHESIS, REFERENCES

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DISCUSSION
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521, 1970
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Recent Developments in the Drug Treatment of Schizophrenia

BY JOHN M. DAVIS, M.D.

The author reviews six topics relevant to the drug schizophrenia; 2) indications for use of antipsychotic
treatment ofschizophrenia. The quantitative drugs; 3) the usefulness of massive doses in irnprovimg
effectiveness ofpromazine is ofinterest ss’ith respect to clinical response in typical acute schizophrenia; 4)
the structural models ofthe phenothiazines and the drug treatment of the phenothiazine-nesistant patient;
dopamine theory ofschizophrenia. The quantitative 5) phemothiazime effectiveness and molecular models;
effectiveness ofantipsvchotic drugs is also important and 6) the effectiveness oftwo new neunoleptic agents,
in evaluating new agents and therefore relevant to a molindone and loxapine. Since the use of the intra-
discussion of two new/v released neuroleptics, muscular depot drugs such as fluphenazine decanoate
molindone and loxapine. The author’s discussion of (a useful strategy for schizophrenic patients who tend
high-dose treatmentfor typical acute schizophrenics to forget to take their pills and an important addition to
or treatment-resistant patients reviews the available clinical therapeutics) has already been reviewed ne-
data and calls attention to thefact that these areas of cently in theAmericanfournalofPsychiatrv (1). I will
pharmacologic research have not received sufficient limit the content of this paper to avoid redundancy.
attention.

Presented at the 128th annual meeting of the American Psychiatric

Association. Anaheim. Calif. . May 5-9, 1975.
SOME RECENT DEVELOPMENTS in the drug treatment of
Dr. Davis is Director of Research, Illinois State Psychiatric Insti-
schizophrenia are relevant to six problems of practical
tute, 1601 West Taylor St., Chicago, Ill. 60612, and Professor of Psy-
importance: 1) the effectiveness of the antipsychotic chiatry. University of Chicago, Pritzker School of Medicine, Chi-
agents as compared with placebo in the treatment of cago. Ill.

208 Am J Psychiatry 133:2, February 1976