The psychedelic model of schizophrenia: the case of N,N-dimethyltryptamine

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.

Abstract

“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.”

Authors: J. Christian Gillin, Jonathan Kaplan, Richard Stillman & Richard J. Wyatt

Summary

The authors review the research on DMT as a possible schizophrenic toxin, but conclude that more data are necessary before the validity of this theory can be determined.

The tramsmethylation hypothesis was first proposed by Osmond and Smythies in 1952, and has been supported by several studies that have shown that methiomine increases the synthesis of an abnormally methylated substance in schizophrenic patients without evidence of organic brain dysfunction.

Several substances have been proposed as causative agents in schizophrenia, including 3,5-dimethoxyphenylethylamime (pink spot), bufotenime, 5-methoxy-N,N-dimethyltryptamime, and N,N-dmethyltryptamime. However, little is known about 5-methoxy-DMT, and the evidence for its role in schizophrenia is limited.

A substance that mimics important clinical aspects of schizophrenia must be found in man, synthesized in man, and differentially synthesized in schizophrenia.

DMT may cause schizophrenia if it sets irreversible changes in progress. Neunoleptic drugs can inhibit the synthesis, increase the metabolism, or amtagomize the behavioral effects of DMT.

DOES DMT PRODUCE SIGNIFICANT SCHIZOPHRENIC-LIKE SYMPTOMS?

Szara (9), Rosenberg (10), Turner and Merl (5) reported that DMT causes visual illusions, hallucinations, distortions of spatial perception and body image, and euphoria.

We administered DMT intramuscularly to 15 male volunteers who were experienced users of psychedelic substances and gave a complete medical history and examination prior to testing.

DMT was a hallucinogen with rapid action and a short duration of effect. The psychological effects were accompanied by mydriasis, tachycandia, and increased blood pressure, and the concentration of DMT fell rapidly to baseline, undetectable levels within 45 to 120 minutes.

IS DMT FOUND IN MAN?

Several investigators have reported the presence of DMT in blood and urine of psychiatric patients, but the concentrations have been extremely low. The origin and significance of the identified DMT is unknown.

IS THE PRECURSOR OF DMT PRESENT IN MAN? CAN DMT BE SYNTHESIZED IN MAN?

DMT is thought to be synthesized from tryptarninc in the lung by an enzyme called NMT. Low MAO activity may be genetically determined and may lead to elevated concentrations of tryptamime, which would favor DMT synthesis.

In vivo human synthesis of DMT has not been convincingly demonstrated to date. A male chronic schizophrenic patient’s blood DMT concentration did not change from its very low placebo values.

IS DMT SYNTHESIZED OR METABOLIZED DIFFERENTLY IN SCHIZOPHRENICS THAN IN CONTROLS?

DMT is rapidly metabolized in man and only 2% of the administered dose is found in the blood at the time of the peak blood concentration. Little knowledge currently exists on the metabolism of DMT in schizophrenics compared with normal control subjects.

The failure of various investigators to find measurable concentrations of DMT in venous blood or urine of schizophremics may be explained by the rapid metabolism of this compound.

DOES TOLERANCE TO DMT DEVELOP?

Schizophrenia lasts for weeks to months in its acute forms and for years to decades in its chronic forms. Tolerance to LSD, mescaline, and psilocybin develops rapidly in man and animals, but not to DMT.

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. The subjects exhibited a variable or aperiodic partial tolerance to DMT.

DO NEUROLEPTICS INHIBIT THE SYNTHESIS, INCREASE THE METABOLISM, OR ANTAGONIZE THE EFFECTS OF DMT?

Although the evidence is currently incomplete, some data suggest that antipsychotic medications may inhibit the activity of NMT. Moreover, some dimethylated metabolites of chiorpromazime may be competitive inhibitors of NMT.

DISCUSSION

Although the DMT model of schizophrenia remains attractive, there is only indirect evidence that it is real. DMT produces striking psychological changes in normal subjects, but the psychological changes induced by DMT do not closely mimic the clima-cal symptoms of schizophrenia.

Arguments can be produced to refute each of these objections, including that DMT’s psychological effect in normal individuals probably should not be cx-pected to mimic schizophrenia.

The author reviews six topics relevant to the drug treatment of schizophrenia, including the quantitative effectiveness of promazine, the dopamine theory of schizophrenia, and two new neuroleptics, molindone and loxapine.

This paper reviews the indications for use of antipsychotic drugs, the usefulness of massive doses, the treatment of the phenothiazine-nesistant patient, phemothiazime effectiveness and molecular models, and the effectiveness of two new neunoleptic agents, molindone and loxapine.