This review (1976) looks a the psychedelic model of schizophrenia, saying that DMT is a schizotonix that mimics symptoms of schizophrenia in healthy individuals. The authors conclude that more data are necessary to determine the validity of this theory.
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.
Earlier theories that schizophrenia might be caused by an endogenous ‘‘schizotoxin’’ motivated searches for methylated psychedelic metabolites that could mimic psychotic symptoms. The transmethylation hypothesis and subsequent work led investigators to consider several candidates, including 3,4-dimethoxyphenylethylamine, bufotenine, 5‑methoxy‑DMT, and N,N‑dimethyltryptamine (DMT). The authors set out to evaluate DMT against a set of criteria (modeled on Koch’s postulates) for a putative schizotoxin: that it mimic key features of schizophrenia; be present in humans along with its precursor; be synthesised endogenously; be differentially synthesised or metabolised in schizophrenia; show incomplete tolerance; and be affected by antipsychotic drugs. Gillin and colleagues review the existing human and animal data on DMT, report their own experimental observations in normal volunteers, and examine biochemical and clinical studies that bear on each criterion. The goal is to judge whether available evidence supports DMT as a causative agent in schizophrenia or whether further data are required.
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The paper is a narrative review that integrates previously published reports with several experimental observations made by the authors. Key empirical elements reported by the authors include: an intramuscular DMT administration study in 15 male volunteers and a tolerance study in 4 male volunteers. The 15 volunteers were experienced users of LSD, mescaline, or other psychedelics, screened by two psychiatrists for absence of psychiatric or physical impairment, and given 0.7 mg/kg DMT intramuscularly. Psychological and autonomic effects were monitored; blood DMT concentrations were measured using a gas chromatographic–mass spectrometric (GC‑MS) isotopic‑dilution assay to correlate pharmacokinetics with psychological effects. GC‑MS is a chemical analysis technique that separates and identifies compounds by chromatography and mass spectrometry. For tolerance, 4 normal male volunteers received 0.7 mg/kg intramuscular DMT twice daily for 5 days; psychological scales, autonomic measures (pupil size, pulse, heart rate), and a simple performance test were used to assess changes over repeated dosing. The authors also summarise animal studies (cats and squirrel monkeys) in which DMT was administered repeatedly to evaluate tolerance; explicit sample sizes for these animal experiments are not provided in the extracted text. In addition to experimental dosing, the authors review analytical studies that sought DMT in human blood and urine, including older less specific assays and later GC‑MS measurements, and biochemical studies of N‑methyltransferase (NMT) activity in human tissues (lung, brain, blood). They report brief clinical challenge observations in single schizophrenic patients given the monoamine oxidase (MAO) inhibitor phenelzine or L‑tryptophan, with measurements of venous DMT concentrations before and during treatment. The analytical and clinical reports are synthesised to address each of the pre‑specified schizotoxin criteria.
Psychological and pharmacokinetic findings in the 15‑subject dosing study: Intramuscular DMT produced rapid onset of effects (within about 5 minutes), peaking at 10–15 minutes and resolving within 45–120 minutes. Major psychological effects were predominantly visual distortions and spatial or colour alterations rather than fully formed visual hallucinations; only one subject reported an auditory hallucination described as a "buzzing bee." Some subjects showed thought blocking; two experienced transient paranoid symptoms lasting under an hour. Peak venous DMT concentrations averaged approximately 100 ng/ml and closely paralleled the psychological and autonomic changes. Concentrations fell rapidly to baseline, undetectable levels within roughly 45–120 minutes after administration. Pharmacokinetic disposition: At the time of peak blood concentration the authors could account for only about 2% of the administered dose in blood; less than 0.01% of the dose was recovered in urine within 24 hours, with most urinary excretion occurring in the first 6 hours. This rapid metabolism and clearance may limit detectability in venous blood and urine. Presence and synthesis in humans: The review of analytic studies indicates that early, less specific assays reported DMT more often than later GC‑MS methods; GC‑MS identifications in humans have occurred but concentrations were extremely low. Positive detections have not been reported more frequently in psychiatric patients or in particular diagnostic groups than in controls. Biochemically, tryptamine (a precursor) and N‑methyltransferase (NMT) activity have been identified in human tissues, notably lung; in vitro conversion of N‑methyltryptamine to DMT in human lung has been demonstrated. MAO activity is reported to be low in platelets of some schizophrenics, which might favour elevated tryptamine levels and thereby DMT synthesis; however, convincing in vivo synthesis of DMT in humans has not been demonstrated. In single‑patient clinical challenges, administration of the MAO inhibitor phenelzine (45–60 mg/day) increased hallucinatory/autistic behaviour in one chronic schizophrenic, but venous DMT concentrations remained at very low placebo values (~0.07 ng/ml). Similarly, L‑tryptophan administration (20 g/day) in another patient did not alter blood DMT or clinical state. Tolerance: Animal data summarised by the authors show no consistent behavioural tolerance in cats given DMT twice daily for 15 days or every 2 hours for 24 hours, and no behavioural tolerance reported in squirrel monkeys given DMT once daily for 38 days (sample sizes not specified in the extracted text). In the human tolerance experiment (n=4), repeated dosing twice daily for 5 days did not consistently change peak blood DMT concentrations, autonomic measures, the number of psychological items endorsed on a scale, or objective errors on a simple performance test. Three of the four volunteers reported diminished subjective "highs" after two to four injections, but responses were variable and did not indicate a clear generalised loss of responsiveness. The authors characterise this as variable or aperiodic partial tolerance. Some prior reports suggested schizophrenics may be less sensitive to DMT than controls, but evidence is limited. Effects of antipsychotic drugs: The authors note indirect biochemical data suggesting that antipsychotic drugs might inhibit NMT activity. Chlorpromazine has been proposed to have such an effect, and dimethylated chlorpromazine metabolites have been reported as competitive inhibitors of NMT. A dialysable inhibitor of NMT was reported in bovine pineal gland, and aqueous bovine pineal extracts have been reported to produce clinical improvement in some schizophrenic patients in other studies. Nonetheless, the influence of antipsychotic medications on DMT metabolism or the behavioural effects of DMT in humans remains poorly characterised in the extracted text.
The authors judge that the DMT model of schizophrenia remains plausible but not proven. Supporting points are that DMT produces robust psychedelic effects in normal subjects; the enzymatic machinery and precursors to synthesise DMT are present in human tissues in vitro; DMT has been intermittently identified in human biological samples; tolerance to DMT appears incomplete; and antipsychotic drugs could conceivably interfere with its synthesis. Against the model, the authors emphasise that significant differences in DMT concentrations between schizophrenic patients and controls have not been demonstrated, convincing in vivo synthesis of DMT in humans has not been shown, and the acute psychological effects of DMT in volunteers do not closely mimic the clinical syndrome of schizophrenia. They note that when DMT has been measured in schizophrenic patients its concentrations were manyfold lower than the blood levels associated with psychedelic effects in experimental subjects. The authors discuss possible rebuttals to these objections that bear on detectability rather than on the model’s substance: DMT is rapidly cleared from blood and excreted in small amounts, so venous assays may underestimate brief arterial exposures, particularly if synthesis occurred in lung and arterial transport delivered DMT directly to brain before substantial venous mixing. They also point out that experimentally administered DMT differs from putative endogenous production in context and expectation, so phenomenological differences between acute experimental effects and chronic psychosis might be expected. Nevertheless, the authors conclude that most positive evidence for the DMT–schizophrenia link is indirect and that decisive tests are lacking. They call for further data to evaluate the hypothesis; the theory’s validity will ultimately depend on the empirical findings it generates.
Several investigators have reported the presence of DMT in blood and urine of psychiatric patients (see table). Positive reports were more common with the GILLIN, KAPLAN, STILLMAN, AND WYATT earlier, less specific methods of analysis than with the later GC-MS techniques. Although DMT has occasionally been identified by GC-MS techniques in some subjects, the concentration has been extremely low. Also, the presence of DMT has not been reported more frequently in patients with particular diagnoses or in psychiatric patients in general compared with normal controls. The origin and significance of the identified DMT is unknown. Although it might reflect endogenous synthesis, it could also result from diet. bacterial products, laboratory error, or other sources. As figureindicates. DMT is thought to be synthesized from tryptamine in a reaction catalyzed by an Nmethyltransferase (NMT). Tryptamine is reportedly present in human lung and elsewhere. NMT activity has been reported in human brainand blood. but its highest activity and specificity is in human lung., using GC-MS techniques, demonstrated in vitro conversion of N-methyltryptamine to DMT in human lung. Wyatt and associatesandhave found that MAO activity in platelets is low in some schizophrenics compared with control subjects, and that this defect may be genetically determined. Low MAO activity may lead to elevated concentrations of tryptamine, which would favor the synthesis of DMT. In vivo human synthesis of DMT has not been convincingly demonstrated to date. We studed 1 male chronic schizophrenic patient before and during administration of 45-60 mg/day of the MAO inhibitor phenelzine. Although the patient was more hallucinatory and autistic on phenelzine than he had been during the placebo period, DMT concentrations in venous blood did not change from their very low placebo values (approximately .07 ng/ml). We also studied another male schizophrenic patient before and during treatment with 20 g/day of L-tryptophan, the biosynthetic precursor of tryptamine. Again, there was no change in blood DMT concentration. The patient's clinical condition was not altered by L-tryptophan.
Synthesis of DMT in man has yet to be conclusively demonstrated, and little knowledge currently exists on the metabolism of DMT in schizophrenics compared with normal control subjects. Szara (9) suggested two major routes of metabolism of DMT: 1) dealkylation and oxidative deamination, leading to indole-3-acetic acid and 2) 6-hydroxylation followed either by glucuronide formation of 6-hydroxy-DMT or by dealkylation and oxidative deamination leading to 6-hydroxyindoleacetic acid. To our knowledge, there have been no studies comparing the concentrations of these metabolites in schizophrenics and controls. Our recent study of the effects of DMT on volunteer subjects (11) suggested that the drug is rapidly metabolized. Assuming that DMT is distributed equally throughout the blood, we could account for only about 2% of the administered dose at the time of the peak blood concentration. Moreover, less than .01% of the administered dose was found in urine within 24 hours, and most of that amount was excreted within the first 6 hours.
Am J Psychiatry 133:2, February 1976 Thus the failure of various investigators to find elevated concentrations of DMT in venous blood or urine of schizophrenics may be explained by the rapid metabolism of this compound. If DMT is actually formed by lung NMT, then schizophrenia is a lung disease, and DMT may be transported directly from lung to brain via the arterial system. Once DMT is exposed to liver, kidney, or muscle, it may be so rapidly metabolized that measurable concentrations cannot be detected in venous blood.
Since schizophrenia is a clinical syndrome that lasts for weeks to months in its acute forms and for years to decades in its chronic forms, a biochemical theory must be able to explain long-term symptoms. The issue of tolerance has been a major problem in the schizotoxin theory of schizophrenia. 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. Also, lack of behavioral tolerance has been reported in squirrel monkeys given DMT once daily for 38 days. More recently, we studied the issue of tolerance in 4 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. Further studies, including longer or more frequent trials with DMT, are necessary to fully evaluate this phenomenon. This type of variable tolerance has also been reported recently by, who studied the suppressive 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.reported that schizophrenics are less sensitive to the effects of DMT than controls. If schizophrenics do show diminished responsiveness to DMT, this may result from increased metabolism or variable tolerance resulting from long-term endogenous synthesis of DMT.
Although the evidence is currently incomplete, there are data suggesting that antipsychotic medications may inhibit the activity of NMT. Axelrodhas suggested that chlorpromazine might have this effect. Moreover, a dialyzable inhibitor of NMT has been reported in bovine pineal gland, which is an interesting finding becauseobtained favorable clinical results in some schizophrenic patients with an aqueous extract of bovine pineal gland. Some dimethylated metabolites of chlorpromazine have also been reported to be competitive inhibitors of NMT. Thus it is conceivable but unproven that antipsychotic drugs inhibit the synthesis of a methylated schizotoxin. Little is known, however, about the influence of antipsychotic medications on the metabolism or behavioral effects of DMT.
Although the DMT model of schizophrenia remains attractive, most of the positive evidence is indirect, supporting the plausibility rather than the reality of the model. DMT does produce striking psychological changes in normal subjects, the enzymes and precursors are present to synthesize it in vitro in human tissue, it has been found occasionally in man, and tolerance to its behavioral effects is incomplete. Moreover, effective antipsychotic treatments may conceivably interfere with the synthesis of DMT. On the other hand, significant differences in DMT concentrations in schizophrenics versus controls have not been proven, in vivo synthesis of DMT in man has not been demonstrated, and the psychological changes induced in man by DMT do not closely mimic the clinical symptoms of schizophrenia. When psychological changes have been produced in normal subjects, this has been with DMT blood concentrations 50 to 100 times greater than those in the few schizophrenic patients in whom DMT has been identified. Arguments can undoubtedly be produced to refute each of these objections. The psychological effect of DMT in normal individuals probably should not be expected to mimic schizophrenia. After all, the volunteer knows what is happening to him when the experimenter administers DMT, but DMT is (hypothetically) synthesized endogenously in schizophrenic patients. The data on DMT in blood and urine may be of dubious relevance in view of its rapid clearance from blood and its failure to appear in appreciable amounts in urine. Like any good scientific theory, the DMT model of schizophrenia will ultimately live or die by the data that it heuristically generates. We hope that, within the foreseeable future, forthcoming data will give this theory either a new lease on life or a decent burial. The author reviews six topics relevant to the drug treatment of schizophrenia. The quantitative effectiveness of promazine is of interest with respect to the structural models of the phenothiazines and the dopamine theory of schizophrenia. The quantitative effectiveness of antipsychotic drugs is also important in evaluating new agents and therefore relevant to a discussion of two newly released neuroleptics, molindone and loxapine. The author's discussion of high-dose treatment for typical acute schizophrenics or treatment-resistant patients reviews the available data and calls attention to the fact that these areas of pharmacologic research have not received sufficient attention. SOME RECENT DEVELOPMENTS in the drug treatment of schizophrenia are relevant to six problems of practical importance: 1) the effectiveness of the antipsychotic agents as compared with placebo in the treatment of 208 Am J Psychiatry 133:2, February 1976 schizophrenia: 2) indications for use of antipsychotic drugs: 3) the usefulness of massive doses in improving clinical response in typical acute schizophrenia; 4) drug treatment of the phenothiazine-resistant patient; 5) phenothiazine effectiveness and molecular models: and 6) the effectiveness of two new neuroleptic agents, molindone and loxapine. Since the use of the intramuscular depot drugs such as fluphenazine decanoate (a useful strategy for schizophrenic patients who tend to forget to take their pills and an important addition to clinical therapeutics) has already been reviewed recently in the American Journal of Psychiatry (1). I will limit the content of this paper to avoid redundancy. Presented at the 128th annual meeting of the American Psychiatric Association, Anaheim. Calif.. May 5-9. 1975.
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