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

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.