The authors review the research on N,N-dimethyltryptamine (DMT) as a possible "schizotoxin". DMT produces psychedelic effects when administered to normal subjects, the means are present to synthesize it in man, it has occasionally been found in man, and tolerance to its behavioral effects is incomplete. However, DMT concentrations have not been proven to differ significantly in schizophrenics and normal controls. Also, in vivo synthesis of DMT has not been convincingly demonstrated, and the psychological changes it produces do not closely mimic the symptoms of schizophrenia. The authors conclude that more data are necessary before the validity of this theory can be determined.

DOES DMT PRODUCE SIGNIFICANT SCHIZOPHRENIC-LIKE SYMPTOMS?

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 hallucinations, distortions of spatial perception and body image, speech disturbances, and euphoria. A striking finding was that the effects of DMT began within 5 minutes and ended within 1 hour after injection. Similar results have since been reported by Rosenberg and associates (10) and Turner and Merlis (5).

In order to reexamine the psychological effects of DMT and to correlate them with pharmacokinetic aspects, we administered .7 mg/kg of DMT intramuscularly to 15 make volunteers. Each subject was an experienced user of LSD, mescaline, or other psychedelic substances who expressed an intention to continue using these agents in the future. All subjects were intereviewed by two psychiatrists and were given a complete medical history and examination prior to testing in order to ensure the absence of psychiatric and physical impairment.

Like previous investigators, we found that DMT was a hallucinogen with rapid action and a short duration of effect. Psychological changes were evident within 5 minutes of injection, peaked at about 10 to 15 minutes, and ended within 45 to 120 minutes. The major psychological effects are shown in table 1. The subjects became so uncommunicative and withdrawn during the drug experience that we were forced to inquire about the subjective effects with simple "yes-no" questions. Although all subjects reported visual distortions and illusions, these were color or spatial distortions rather than formed visual hallucinations. Only 1 subject reported an auditory hallucination, a "buzzing bee" in his ear. We did not observe formal loosening of associations, although several subjects seemed to have thought blocking. Two subjects had paranoid symptoms that lasted less than an hour.

These psychological changes were accompanied by mydriasis, tachycardia, and increased blood pressure. Blood levels of DMT (see figure 2), assayed by a gas chromatographic-mass spectrometric (GC-MS) isotopic dilution technique, closely paralleled the psychological and autonomic changes (11). Peak concentrations of DMT, which averaged approximately 100 ng/ml, were reached about 10 to 15 minutes after injection; the concentration then fell rapidly to baseline, undetectable levels within about 45 to 120 minutes after administration.

TABLE 1.

Subjective Effects of DMT Experienced by 15 Normal Volunteer Subjects
Subjective Effects	Percent
Visual hallucinations	100
Hallucinations with eyes closed	100
Movement of surroundings	93
Difficulty talking	93
Difficulty describing feelings	93
Relaxation	93
Difficulty concentrating	93
Colors seem brighter	87
Excitation	87
Thinking faster	87
Dry mouth	87
Tenseness	80
People look different	75
Depersonalization	60
Nausea	60
People have orange-red hue	53
Hallucinating "real things"	27
Paranoia	20
Auditory hallucinations	7

FIGURE 2.

Mean DMT Concentrations in Whole Blood Following Injection of DMT in 15 Normal Volunteers.

 140+
    |
    |
    |         +
 120+         |           Blood DMT Concentrations (ng/ml)
    |         |
    |         |
    |         |
 100+         *
    |        .|.
    |       ..|.
    |       . | .
  80+       . | .
    |    + .  +  .
    |    | .     . +
    |    | .      .|
  60+    |.        |
    |    |.        *
    |    *         |.
    |   .|         | .
  40+   .|         +  .
    |  . |              .           
    |  . |                . .    +
    |  . +                    . .* . . . . .
  20+ .                          +            . . . .          +
    | .                                               . . . . .*. | . 
                                                          +  . |.     
                                                             .
   0*---------+--------+---------+---------+---------+---------+--//--
   ----
    0        10       20        30        40       50        60 // 
    120
                      Time After Injection (minutes)

DOES TOLERANCE TO DMT DEVELOP?

Tolerance to LSD, mescaline and psilocybin develops rapidly in man and animals, for some if not all behavioral effects.

In our initial efforts, we found that tolerance did not develop to unconditioned behavioral and EEG effects of DMT in cats administered DMT twice daily for 15 days or every 2 hours for 24 hours (34). Also, lack of behavioral tolerance has been reported in squirrel monkeys given DMT once daily for 38 days (35).

More recently, we studied the issue of tolerance in normal male volunteers who received 0.7 mg/kg of DMT intramuscularly twice daily for 5 days. Repeated administration did not consistently alter the peak blood concentration of DMT; autonomic changes in pupil size, pulse, or heart rate; the number of psychological items changed in a psychological scale; or the frequency of errors in a test requiring the subject to cross out a specific number in a list of random numbers. Three of the 4 subjects reported diminished subjective "highs" on a scale of 0 to 10 after two to four injections of DMT, but their subjective responses were variable from trial to trial and did not indicate a general loss of responsiveness to DMT. Rather, these subjects exhibited a variable or aperiodic partial tolerance to DMT. This pattern is reminiscent of Koella and associates' report of a cyclic change in ambulation produced by LSD in goats (36). Further studies, including longer or more frequent trials with DMT, are neccesary to fully evaluate this phenomenon.

This type of variable tolerance has also been reported recently by Kovacic and Domino(37), who studied the supressive effects of DMT on the operant behavior of appetitively conditioned rats who were given DMT every 2 hours for periods of up to 21 days.

Boszormenyi and Szara (38) reported that schizophrenics do show diminished responsiveness to DMT, this may result from increased metabolism or variable tolerance resulting from long-term endogenous synthesis of DMT.

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